Utilization of pyrimidine derivatives for preventing and treating cerebral ischaemia

ABSTRACT

Use of pyrimidine derivatives of the formula Iwhere the substituents are as defined in the description, and of their physiologically tolerated salts for producing medicaments for the prophylaxis and treatment of cerebral ischemia and strokes.

This is a 371 of PCT/EP99/10369 filed Dec. 24, 1999.

The invention relates to the use of pyrimidine derivatives for theprophylaxis and therapy of cerebral ischemia.

DE 1936769.7 describes 3-substituted 3,4,5,6,7,8-hexahydro-pyrido[4′,3′:4,5] thieno [2,3-d] pyrimidine derivatives of the formula I

where

R¹ is hydrogen, a C₁-C₄-alkyl group, an acetyl or benzoyl group, aphenylalkyl C₁-C₄ radical, with the aromatic moiety optionally beingsubstituted by halogen, or C₁-C₄-alkyl, trifluoromethyl, hydroxyl,C₁-C₄-alkoxy, amino, cyano or nitro groups, a naphthylalkyl C₁-C₃radical, a phenylalkanone C₂-C₃ radical or a phenylcarbamoylalkyl C₂radical, with it being possible for the phenyl group to be substitutedby halogen,

R² is a phenyl, pyridyl, pyrimidinyl or pyrazinyl group which isoptionally monosubstituted, disubstituted or trisubstituted by halogenatoms, C₁-C₄-alkyl or trifluoromethyl, trifluoromethoxy, hydroxyl,C₁-C₄-alkoxy, amino, monomethylamino, dimethylamino, cyano or nitrogroups and which can optionally be fused to a benzene nucleus which canoptionally be monosubstituted or disubstituted by halogen atoms,C₁-C₄-alkyl or hydroxyl, trifluoromethyl, C₁-C₄-alkoxy, amino, cyano ornitro groups and can optionally contain 1 nitrogen atom, or to a 5- or6-membered ring which can contain 1-2 oxygen atoms, or can be optionallysubstituted by a phenyl-C₁-C₂-alkyl- or alkoxy group, with it beingpossible for the phenyl radical to be substituted by halogen, or amethyl, trifluoromethyl or methoxy group,

A is NH or oxygen,

B is hydrogen or methyl,

C is hydrogen, methyl or hydroxyl,

X is nitrogen,

Y is CH₂, CH₂—CH₂, CH₂—CH₂—CH₂ or CH₂—CH,

Z is nitrogen, carbon or CH, with it also being possible for the bondbetween Y and Z to be a double bond,

and n is the number 2, 3 or 4.

These compounds of the formula I can be prepared by reacting a compoundof the formula II

in which R¹ has the abovementioned meaning, R³ is a cyano group or aC₁₋₃-alkyl-carboxylic ester group, R⁴ is C₁₋₃-alkyl and C is hydrogen,methyl or hydroxyl, with a primary amine of the formula III

where R² and B have the abovementioned meanings, and, where appropriate,converting the resulting compound into the acid addition salt of aphysiologically tolerated acid.

The reaction expediently takes place in an inert organic solvent, inparticular a lower alcohol, e.g. methanol or ethanol, or a cyclic,saturated ether, in particular tetrahydrofuran or dioxane, or withoutany solvent.

As a rule, the reaction takes place at from 20 to 190° C., in particularfrom 60 to 90° C., and has generally finished within from 1 to 10 hours.

Or, a compound of the formula II

where R¹ has the abovementioned meanings, R³ is a cyano group or aC₁₋₃-alkyl-carboxylic ester group, R⁴ is C₁₋₃-alkyl and C is hydrogen,methyl or hydroxy, is reacted with a primary amine of the formula IV

where B has the abovementioned meanings, in an inert solvent, preferablyalcohols, such as ethanol, at from 60 to 120° C., to give thecyclization product V (D=OH)

which is then converted with a halogenating agent, such as thionylchloride or hydrobromic acid, in an organic solvent such as ahalogenohydrocarbon, or without any solvent, at from room temperature to100° C., into the corresponding halogen derivative V (D=Cl, Br).Finally, the halogen derivative of the formula V (D=Cl, Br) is reactedwith an amine of the formula VI

where X, Y, Z and R² have the abovementioned meanings, to give the novelend product of the formula I. This reaction proceeds most efficiently inan inert organic solvent, preferably toluene or xylene, in the presenceof a base, such as potassium carbonate or potassium hydroxide, and atfrom 60 to 150° C.

The novel compounds of the formula I can be purified either byrecrystallization from the customary organic solvents, preferably from alower alcohol, such as ethanol, or by means of column chromatography.

The free 3-substituted pyrido[4′,3′:4, 5]thieno[2,3-d]-pyrimidinederivatives of the formula I can be converted, in the customary manner,into the acid addition salts of a solution using the stoichiometricquantity of the corresponding acid. Examples of pharmaceuticallytolerated acids are hydrochloric acid, phosphoric acid, sulfuric acid,methanesulfonic acid, amidosulfuric acid, maleic acid, fumaric acid,oxalic acid, tartaric acid or citric acid.

The following Examples serve to clarify the invention:

A Preparation of the starting materials of the formulae II, V and VI

The2-amino-3-carboethoxy(cyano)-4,5,6,7-tetrahydrothieno-[2,3-c]pyridineshaving a methyl, benzyl, acetyl or benzoyl group in the 6 position orhaving a 6 position which is unsubstituted, which are employed asstarting materials, are known from the literature (K. Gewald et al.).

a)2-Ethoxymethyleneamino-3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

3.5 ml of acetic anhydride were added to 46.0 g (238 mmol) of2-amino-3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]-pyridine in 250ml of triethyl orthoformate and the mixture was boiled under nitrogenand at reflux for 4 h. After that, the mixture was filtered off withsuction, in the hot, through a suction filter and the filtrate wasevaporated right down at 80° C. on a rotary evaporator. The residue wastaken up in 300 ml of methyl t-butyl ether and this mixture was heatedto boiling. After the insoluble solids had been filtered off withsuction, 45.4 g (77%) of the product crystallized out in an icebath withstirring. A further 1.7 g (3%) of product were obtained from the motherliquor as a second fraction. m.p.: 88-89° C.

b)2-Ethoxymethyleneamino-3-carboethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

3.2 ml of acetic anhydride were added to 40.0 g (167 mmol) of 52-amino-3-carboethoxy-6-methyl-4,5,6,7-tetrahydrothieno-[2,3-c]pyridinein 250 ml of triethyl orthoformate and the mixture was boiled undernitrogen and at reflux for 3 h. After that, the mixture was evaporatedright down at 80° C. on a rotary evaporator. 48.0 g (97%) of crudeproduct were isolated as a dark oil, which is sufficiently pure forfurther reaction.

c)2-Amino-3-carboethoxy-6-(4-chloro)benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

25.6 g (204 mmol) of 4-chlorobenzyl chloride and 12.4 g (90 mmol) offinely powdered potassium carbonate were added to 20.4 g (90.2 mmol) of2-amino-3-carboethoxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine in 250 mlof tetrahydrofuran and the mixture was boiled at reflux for 3 h. Afterthat, the mixture was evaporated right down on a rotary evaporator. Theresidue was partitioned between methyl t-butyl ether and water, afterwhich the phases were rendered alkaline with sodium hydroxide solutionand the organic phase was then washed with water and evaporated. Thecrude product was dissolved in 100 ml of hot ethanol and was left tocrystallize while stirring. 20.5 g (65%) of product having a m.p. of134-135° C. were isolated.

d)2-Ethoxymethyleneamino-3-carboethoxy-6-(4-chloro)benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

2.0 ml of acetic anhydride were added to 19.3 g (55.0 mmol) of2-amino-3-carboethoxy-6-(p-chlorobenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridinein 125 ml of triethyl orthoformate and the mixture was boiled undernitrogen and at reflux for 1 h. After that, the mixture was evaporatedright down at 80° C. on a rotary evaporator. 21.9 g (98%) of crudeproduct were isolated as a dark oil, which is sufficiently pure forfurther reaction.

e)2-Amino-3-carboethoxy-6-(3-phenyl)propyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

9.0 g (45 mmol) of 1-phenyl-3-bromopropane, 400 mg of potassium iodideand 6.1 g (44.2 mmol) of finely powdered potassium carbonate were addedto 10.0 g (44.2 mol) of2-amino-3-carboethoxy-4,5,6,7-tetrahydrothieno[2,3-c)pyridine in 100 mlof xylene and the mixture was boiled at reflux for 6 h. Followingevaporation on a rotary evaporator, the residue was taken up in waterand this mixture was adjusted to pH=10 and extracted twice withmethylene chloride. After the organic phase had been dried andevaporated, the crude product was thoroughly stirred in 50 ml ofisopropanol. The pale solids were filtered off with suction and rewashedwith isopropanol. 7.8 g (51%) of product having a m.p. of 108-110° C.were isolated.

The additional 4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivatives whichare substituted in the 6 position were prepared in analogy with c) ande), e.g.:

2-Amino-3-carboethoxy-6-ethyl-4,5,6,7-tetrahydrothieno-[2,3-c]pyridine,m.p. 74-76° C.

2-Amino-3-carboethoxy-6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

2-Amino-3-carboethoxy-6-benzyl-4,5,6,7-tetrahydrothieno-[2,3-c]pyridine,m.p. 116-118° C.

2-Amino-3-carboethoxy-6-(4-methyl)benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

2-Amino-3-carboethoxy-6-(4-nitro)benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine,m.p. 170-172° C.

2-Amino-3-carboethoxy-6-(4-methoxy)benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine,m.p. 154-156° C.

2-Amino-3-carboethoxy-6-(2-phenyl)ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine,m.p. 80-83° C.

2-Amino-3-carboethoxy-6-(2-(4-methoxyphenyl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine,m.p. 76-78° C.

2-Amino-3-carboethoxy-6-(2-(4-chlorophenyl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine,m.p. 102-105° C.

2-Amino-3-carboethoxy-6-(3-(4-chloro)phenyl)propyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

2-Amino-3-carboethoxy-6-(4-phenyl)butyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

2-Amino-3-carboethoxy-6-(3-benzoyl)propyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

2-Amino-3-carboethoxy-6-(2-benzoylamino)ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine,m.p. 190-192° C.

2-Amino-3-carboethoxy-6-(2-(N-benzoyl)aminoethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

2-Amino-3-carboethoxy-6-(3-benzoylamino)propyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

f) EthylN-(3-carboethoxy-6-methyl-4,5,6,7-tetrahydrothieno-[2,3-c]pyridin-2-yl)ethaneimidate

0.8 ml of acetic anhydride was added to 3.0 g (12.5 mmol) of2-amino-3-carboethoxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine in 25 mlof triethyl orthoacetate and the mixture was boiled under nitrogen andat reflux for 2 h. After that, the mixture was evaporated right down at80° C. on a rotary evaporator. 3.6 g (93%) of crude product wereisolated as a dark oil, which is sufficiently pure for further reaction.

g)2-Carboethoxyamino-3-carboethoxy-6-acetyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

3.0 g (28 mmol) of ethyl chloroformate and 2.6 g (18.6 mmol) of finelypowdered potassium carbonate were added to 5.0 g (18.6 mmol) of2-amino-3-carboethoxy-6-acetyl-4,5,6,7-tetrahydrothieno-[2,3-c]pyridinein 50 ml of toluene and the mixture was boiled at reflux for 2 h. Afterthat, the reaction mixture was taken up in ice/water, after which thetoluene phase was separated off and the aqueous phase was reextractedwith toluene. After drying, the combined organic phases were evaporated.5.8 g (92%) of product were isolated as an oil, which slowlycrystallizes to some degree.

h)3,4,5,6,7,8-Hexahydro-3-(2-hydroxy)ethyl-7-methylpyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one

17.6 ml (292 mmol) of ethanolamine were added to 86.4 g (292 mmol) of2-ethoxymethyleneamino-3-carboethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridinein 200 ml of ethanol and the mixture was boiled at reflux for 2 h. Themixture was then evaporated in vacuo and the residue was taken up in 30ml of ethyl acetate while stirring. The solids which precipitated outovernight were filtered off with suction and rewashed with a littleethyl acetate. After recrystallizing from ethanol, 48.0 g (62%) ofproduct having a m.p. of 163-165° C. were isolated.

2,4,5,6,7,8-Hexahydro-3-(2-chloro)ethyl-7-methylpyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one

42.0 g (158 mmol) of3,4,5,6,7,8-hexahydro-3-(2-hydroxy)-ethyl-7-methylpyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-onein 240 ml of 1,2-dichloroethane were heated to reflux, after which 12.7ml (175 mmol) of thionyl chloride in 20 ml of 1,2-dichloroethane wereadded dropwise. After 2 h of boiling at reflux, the reaction mixture wasallowed to cool and was poured onto ice/water. The mixture waspartitioned, at pH=10, between methylene chloride and water, and theaqueous phase was reextracted with methylene chloride. After drying, thecombined organic phases were evaporated. The crude product (40 g) wasrecrystallized from 400 ml of isopropanol. 30.5 g (68%) of producthaving a m.p. of 159-161° C. were isolated.

The following were prepared in analogy with h) and i):

3,4,5,6,7,8-Hexahydro-3-(1-hydroxy)prop-2-yl-7-methylpyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one

3,4,5,6,7,8-Hexahydro-3-(1-chloro)prop-2-yl-7-methylpyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one

3,4,5,6,7,8-Hexahydro-3-(2-hydroxy)propyl-7-methylpyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,m.p. 158-160° C.

3,4,5,6,7,8-Hexahydro-3-(2-chloro)propyl-7-methylpyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one

k) N-(1-Naphthyl)piperazine

83.2 g (966 mmol) of piperazine, 38.0 g (339 mmol) of potassiumtert-butoxide and 50.0 g (241 mmol) of 1-bromonaphthalene were added toa mixture of 5.4 g (24.2 mmol) of palladium acetate and 14.7 g (48.3mmol) of tri-o-tolylphosphine in 500 ml of xylene and the reactionmixture was heated at reflux for 10 h under a nitrogen atmosphere andwhile stirring thoroughly. After that, the mixture was diluted withmethylene chloride, the insoluble residues were filtered off and thefiltrate was evaporated. The crude product was purified by columnchromatography (silica gel, eluent THF/methanol/ammonia 85/13/2). 21.5 g(42%) of product having a m.p. of 84-86° C. were isolated.

l) N-(2-Methyl-1-naphthyl)piperazine

14.7 g (82.7 mmol) of bis(2-chloroethyl)amine×HCl were added to 13.0 g(82.7 mmol) of 1-amino-2-methylnaphthalene in 100 ml of chlorobenzeneand the mixture was boiled under nitrogen and at reflux for 90 h. Themixture was then evaporated and the residue was partitioned betweenmethylene chloride and water at pH=9, and the organic phase wasevaporated after having been dried. The crude product was purified bycolumn chromatography (silica gel, eluent THF/methanol/ammonia,85/13/2). 11.6 g (62%) of product were isolated.

m) 4-Piperazin-1-ylisoquinoline

4.51 g (21.7 mmol) of 4-bromoisoquinoline, 4.65 g (25.0 mmol) of t-butylpiperazine-N-carboxylate, 0.1 g (0.11 mmol) oftris(dibenzylideneacetone)dipalladium, 0.11 g (0.18 mmol) of2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 2.92 g (30.4 mmol) ofsodium t-butoxide were together added to 50 ml of toluene and themixture was stirred at 75° C. for 2 h. The reaction mixture was added toice/sodium chloride and the latter mixture was extracted with ethylacetate; the organic phase was dried over sodium sulfate and the solventwas removed on a rotary evaporator. The product crystallized out and wasfiltered off with suction and washed with pentane. This resulted in 5.5g (81%) of the Boc-protected piperazine (m.p.: 111° C.). 5.2 g (16.6mmol) of this substance were taken up in 17 ml of dichloromethane, afterwhich 17 ml (0.22 mmol) of trifluoroacetic acid were slowly added at 0°C. The mixture was left to stir at 0° C. for 4 h and was then pouredonto ice water and this latter mixture was extracted withdichloromethane. The aqueous phase was filtered, rendered alkaline andextracted with dichloromethane. After drying over sodium sulfate and toa large extent removing the solvent, dilution was carried out withdiethyl ether, and the hydrochloride was precipitated with etherealhydrochloric acid. This afforded 3.2 g (67%) of the product having am.p. of 293-294° C.

Insofar as they were not known from the literature (cf. PatentApplication DE 19636769.7 as well), additional piperazine derivatives(see Examples) were prepared in analogy with k), l) and m).

B Preparation of the end products

EXAMPLE 13,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-imine×3HCl

3.3 g (12.1 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)-piperazinewere added to 3.0 g (12.1 mmol) of2-ethoxymethylene-amino-3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridinein 60 ml of ethanol and the mixture was boiled at reflux for 3 h. Afterthat, the mixture was evaporated on a rotary evaporator and the residuewas taken up in 100 ml of ethyl acetate. The trihydrochloride wasprecipitated, while stirring, by adding ethereal hydrochloric acid,after which the product was filtered off with suction under nitrogen andwas rewashed with ethyl acetate. After drying at 50° C. in a vacuumcabinet, 3.6 g (55%) of product having a decomposition point of 282-284°C. were isolated.

EXAMPLE 23,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×3HCl

2.4 g (10.2 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)-piperazinewere added to 3.0 g (12.1 mmol) of2-ethoxymethylene-amino-3-carboethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]-pyridinein 50 ml of ethanol and the mixture was boiled at reflux for 3 h. Afterthat, the mixture was evaporated on a rotary evaporator and the crudeproduct was purified by column chromatography (silica gel, eluentmethylene chloride/methanol, 93/7). The free base was converted into thetrichloride (3.2 g, 48%), having a decomposition point of 288-290° C.,as above.

EXAMPLE 33,4,5,6,7,8-Hexahydro-7-(4-chlorobenzyl)-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×3HCl

2.0 g (8.6 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)-piperazine wereadded to 3.5 g (8.6 mmol) of2-ethoxymethylene-amino-3-carboethoxy-6-(4-chlorobenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine in 60 ml of ethanol and the mixture was boiled at refluxfor 4 h. After that, the mixture was evaporated on a rotary evaporatorand the crude product was purified by column chromatography (silica gel,eluent methylene chloride/methanol 95/5). The free base was convertedinto the trihydrochloride (3.2 g, 57%), having a decomposition point of290-293° C., as above.

EXAMPLE 43,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-methoxyphenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×3HCl×2 H₂O

3.0 g (11.8 mmol) of 1-(3-aminopropyl)-4-(2-methoxyphenyl)-piperazinewere added to 3.5 g (11.8 mmol) of2-ethoxymethylene-amino-3-carboethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridinein 40 ml of ethanol and the mixture was boiled at reflux for 2 h. Afterthat, the mixture was evaporated on a rotary evaporator and the crudeproduct was purified by column chromatography (silica gel, eluentmethylene chloride/methanol 93/7). The free base was converted into thetrihydrochloride (3.1 g, 44%), having a decomposition point of 122-124°C., as above.

EXAMPLE 53,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-pyridin-2-yl)piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-imine×4HCl×H₂O

2.65 g (12.1 mmol) of 1-(3-aminopropyl)-4-pyridin-2-yl-piperazine wereadded to 3.0 g (12.1 mmol) of2-ethoxymethylene-amino-3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridinein 60 ml of ethanol and the mixture was boiled at reflux for 6 h. Afterthat, the mixture was evaporated on a rotary evaporator and the crudeproduct was taken up in 100 ml of ethyl acetate. The solids whichcrystallized overnight were converted into the tetrahydrochloride, asabove. 2.7 g (38%) of product having a decomposition point of 261-264°C. were isolated.

EXAMPLE 63,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-thiomethylphenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-imine×3HCl

3.2 g (12.1 mmol) of 1-(3-aminopropyl)-4-(2-thiomethylphenyl)-piperazinewere added to 3.0 g (12.1 mmol) of2-ethoxymethylene-amino-3-cyano-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridinein 50 ml of ethanol and the mixture was boiled at reflux for 4 h. Afterthat, the mixture was evaporated on a rotary evaporator and the residuewas taken up in 100 ml of ethyl acetate while heating to boiling. Aftercooling, the insoluble constituents were filtered off and thetrihydrochloride was precipitated in the filtrate, while stirring, byadding ethereal hydrochloric acid; the product was filtered off withsuction under nitrogen and rewashed with ethyl acetate. The crudeproduct (5.1 g) was then recrystallized from methanol. 3.8 g (54%) ofproduct having a m.p. of 306-307° C. were isolated.

EXAMPLE 73,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-pyridin-2-yl-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×3HCl×2H₂O

1.6 g (10.0 mmol) of 1-(2-pyridyl)piperazine, 1.4 g (10.0 mmol) offinely powdered potassium carbonate and 400 mg of potassium iodide wereadded to 2.2 g (7.8 mmol) of3,4,5,6,7,8-hexahydro-3-(2-chloro)ethyl-7-methylpyrido[4′,3′:4,5]thieno[2,3-d]-pyridimin-4-onein 50 ml of xylene and the mixture was boiled at reflux for 24 h. Afterthat, the mixture was evaporated on a rotary evaporator and the residuewas partitioned between methylene chloride and water at pH=10. Theaqueous phase was reextracted once again with methylene chloride and thecombined organic phases were evaporated after having been dried. Thecrude product was purified by column chromatography (silica gel, eluentacetone). This resulted in the isolation of 2.3 g (72%) of product,which was dissolved in 100 ml of ethyl acetate and converted into thehydrochloride, having a m.p. of 233-235° C., using an HCl/ethyl acetatesolution.

EXAMPLE 83,4,5,6,7,8-Hexahydro-7-methyl-3-[1-(4-(1-naphthyl)piperazin-1-yl)prop-2-yl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×3HCl×2H₂O

2.1 g (10.0 mmol) of 1-(1-naphthyl)piperazine, 1.4 g (10.0 mmol) offinely powdered potassium carbonate and 250 mg of potassium iodide wereadded to 2.7 g (9.0 mmol) of3,4,5,6,7,8-hexahydro-3-(1-chloro)prop-2-yl-7-methylpyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-onein 50 ml of xylene and the mixture was boiled at reflux for 70 h. Afterthat, the mixture was evaporated on a rotary evaporator and the residuewas partitioned between methylene chloride and water at pH=10. Theaqueous phase was reextracted once again with methylene chloride and thecombined organic phases were evaporated after having been dried. Thecrude product was purified by column chromatography (silica gel, eluentacetone). This resulted in the isolation of 1.6 g (38%) of product,which was dissolved in ethyl acetate and converted into thehydrochloride, having a m.p. of 242-244° C., using an HCl/ethyl acetatesolution.

EXAMPLE 93,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×3HCl

3.5 g (18.0 mmol) of 1-(2-methoxyphenyl)piperazine; 1.4 g (10.0 mmol) offinely powdered potassium carbonate and 400 mg of potassium iodide wereadded to 2.9 g (8.9 mmol) of3,4,5,6,7,8-hexahydro-3-(2-chloro)propyl-7-methylpyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-onein 60 ml of xylene and the mixture was boiled at reflux for 100 h. Afterthat, the mixture was evaporated on a rotary evaporator and the residuewas partitioned between methylene chloride and water at pH=10. Theaqueous phase was reextracted once again with methylene chloride and thecombined organic phases were evaporated after having been dried. Thecrude product was purified by column chromatography (silica gel, eluentacetone). This resulted in the isolation of 1.0 g (25%) of product,which was dissolved in 100 ml of ethyl acetate and was converted intothe hydrochloride, having a m.p. of 190-192° C. (decomp.), using anHCl/ethyl acetate solution.

EXAMPLE 103,4,5,6,7,8-Hexahydro-2,7-dimethyl-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one

1.5 g (6.2 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)-piperazine wereadded to 1.9 g (6.2 nmol) of ethylN-(3-carboethoxy-6-mathyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-ethaneimidatein 30 ml of ethanol and the mixture was boiled at reflux for 7 h. Afterthat, the mixture was evaporated on a rotary evaporator and the residuewas taken up in 20 ml of ethyl acetate. 2.1 g of crude productcrystallized out overnight and was filtered off with suction andpurified by column chromatography (silica gel, eluent methylenechloride/methanol 92/8). 0.8 g (29%) of product was isolated.

EXAMPLE 113,4,5,6,7,8-Hexahydro-2-hydroxy-7-acetyl-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one

2.5 g (7.3 mmol) of2-carboethoxyamino-3-carboethoxy-6-acetyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridineand 1.7 g (7.3 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazinewere heated at 180° C. for 2 h under nitrogen and with the melt beingthoroughly stirred. After cooling, the crude product was purified bycolumn chromatography (silica gel, eluent methylene chloride/methanol95/5). 0.7 g (20%) of product having a m.p. of 135-137° C. was isolated.

EXAMPLE 123,4,5,6,7,8-Hexahydro-7-acetyl-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one

5.5 g (23.4 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)-piperazinewere added to 5.8 g (23.4 nmol) of2-ethoxymethylene-amino-3-carboethoxy-6-acetyl-4,5,6,7-tetrahydrothieno[2,3-c]-pyridinein 50 ml of ethanol and the mixture was boiled at reflux for 2 h. Afterthat, the mixture was evaporated on a rotary evaporator and the residuewas taken up in 30 ml of ethyl acetate, after which this mixture washeated to boiling and allowed to cool while being stirred. The solidswhich crystallized out were filtered off with suction, after cooling inan icebath, and rewashed with ethyl acetate. 8.7 g (80%) of producthaving a m.p. of 170-172° C. were isolated.

EXAMPLE 133,4,5,6,7,8-Hexahydro-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)-ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one

4.0 g (8.6 mmol) of3,4,5,6,7,8-hexahydro-7-acetyl-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-onewere dissolved in 80 ml of 10% strength hydrochloric acid and thissolution was stirred at a bath temperature of 100° C. for 2 h. Afterthat, the mixture was poured onto ice water and this mixture wasrendered alkaline with conc. sodium hydroxide solution and extractedtwice with methylene chloride. The combined organic phases were driedand evaporated. This resulted in the isolation of 3.7 g of crude productwhich was then recrystallized from 50 ml of isopropanol. 2.4 g (66%) ofproduct having a m.p. of 168-170° C. were obtained.

EXAMPLE 143,4,5,6,7,8-Hexahydro-7-(2-(1-naphthyl)ethyl)-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×3HCl

0.8 g (3.4 mmol) of 2-bromo-1-naphth-1-ylethane and 0.3 g (2.4 mmol) offinely powdered potassium carbonate were added to 1.0 g (2.3 mmol) of3,4,5,6,7,8-hexahydro-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-onein 35 ml of xylene and the mixture was boiled at reflux for 12 h. Afterthat, the mixture was evaporated on a rotary evaporator and the residuewas partitioned at pH=10 between methylene chloride and water. Theaqueous phase was reextracted once again with methylene chloride. Thecombined organic phases were evaporated after having been dried. 2.7 gof crude product were obtained as a dark oil which was purified bycolumn chromatography (silica gel, eluent methylene chloride/acetone7/3). After conversion into the hydrochloride in ethyl acetate, 1.0 g(63%) of product having a m.p. of 293-295° C. (decomp.) was isolated.

The following were prepared in analogy with Examples 1 to 14:

15.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-methoxyphenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-imine,m.p. 112-114° C.

16.3,4,5,6,7,8-Hexahydro-7-benzyl-3-[3-(4-(2-methoxyphenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-imine×2HCl, m.p. 258-261° C. (decomp.)

17.3,4,5,6,7,8-Hexahydro-7-benzyl-3-[2-(4-phenylpiperazin-1-yl)-ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-imine,m.p. 168-170° C.

18.3,4,5,6,7,8-Hexahydro-7-benzyl-3-[3-(4-(2-methoxyphenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 66-67° C.

19.3,4,5,6,7,8-Hexahydro-7-benzyl-3-[2-(4-phenylpiperazin-1-yl)-ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,m.p. 70-71° C.

20.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-pyrimidin-2-yl-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-iminetritartrate, m.p. 112-114° C. (decomp.)

21.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(3-methoxyphenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-imine×3HCl×2 H₂O, m.p. 268-270° C. (decomp.)

22.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-naphth-1-ylpiperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-imine×3HCl , m.p. 250-253° C. (decomp.)

23.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-nitrophenyl)piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-imine×3HCl×2 H₂O, m.p. 271-273° C. (decomp.)

24.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-methylphenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-imine×3HCl, m.p. 280-282° C. (decomp.)

25.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-aminophenyl)piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-imine×HCl×4H₂O, m.p. 113-115° C. (decomp.)

26.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-chlorophenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-imine×3HCl , m.p. 261-263° C. (decomp.)

27.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-pyrimidin-2-ylpiperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 146-148° C.

28.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-benzylpiperidin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-imine×3HCl , m.p. 295-297° C. (decomp.)

29.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-hydroxyphenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-imine,m.p. 164-166° C.

30.3,4,5,6,7,8-Hexahydro-7-methyl-3-[4-(4-(2-methoxyphenyl)-piperazin-1-yl)butyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-imine×HCl×3H₂O, m.p. 272-274° C. (decomp.)

31.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-ethoxyphenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-imine×3HCl×3 H₂O, m.p. 284-286° C. (decomp.)

32.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-ethylphenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-imine×3HCl , m.p. 303-305° C. (decomp.)

33.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-cyanophenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×2HCl×H₂O, m.p. 136-138° C. (decomp.)

34.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-phenylpiperidin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-imine×3HCl , m.p. 280-282° C. (decomp.)

35.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-pyrazin-2-ylpiperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-imine×4HCl×H₂O, m.p. 284-286° C. (decomp.)

36.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-pyrimidin-2-yl-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-imine,m.p. 161-163° C.

37.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(2-cyanophenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-imine,m.p. 148-150° C.

38.3,4,5,6,7,8-Hexahydro-7-benzyl-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×3HCl×H₂O, m.p. 288-290° C. (decomp.)

39.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(3,4-methylenedioxy-phenyl)piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-imine×3HCl, m.p. 288-290° C. (decomp.)

40.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methylphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×2HCl×H₂O,m.p. >300° C.

41.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-chlorophenyl)-piperazin-1-yl)-ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×2HCl×H₂O,m.p. >300° C.

42.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3,4-dimethylphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×2HCl,m.p. 307-310° C.

43.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2,6-dimethylphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×2HCl,m.p. 297-300° C.

44.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2,3-dimethylphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,m.p. 163-167° C.

45.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2,4-dimethylphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×2HCl,m.p. 300-303° C.

46.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3,5-dichlorophenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,m.p. 97-100° C.

47.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2,4-dimethoxyphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×2HCl,m.p. 287-290° C.

48.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×2HCl,m.p. 309-312° C.

49.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-naphth-1-ylpiperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×2HCl×H₂O,m.p. 298-300° C. (decomp.)

50.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(3-hydroxyphenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-imine×2HCl×2H₂O,m.p. 182-184° C. (decomp.)

51.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxy-5-chlorophenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×3HCl,m.p. 170-172° C. (decomp.)

52.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2,5-dimethoxyphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×3HCl×H₂O,m.p. 176-178° C. (decomp.)

53.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxy-5-phenyl-phenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×H₂O,m.p. 79-80° C.

54.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxyphenyl)3,4-dehydropiperidin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×2HCl×2H₂O,m.p. 182-185° C. (decomp.)

55.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-hydroxyphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×2HCl×H₂O,m.p. 281-283° C. (decomp.)

56.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(7-methoxynaphth-1-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×2HCl×H₂O,m.p. 272-274° C. (decomp.)

57.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-naphth-1-ylpiperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-imine×3HCl,m.p. 288-289° C. (decomp.)

58.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(4,5-methylenedioxybenzyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-imine×4HCl×2H₂O,m.p. 249-251° C. (decomp.)

59.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(6-isopropylpyrimidin-4-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-imine×3HCl×2H₂O,m.p. 250-253° C. (decomp)

60.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxynaphth-1-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×2HCl×2H₂O,m.p. 241-243° C. (decomp.)

61.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxyphenyl)-piperidin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×2HCl×2H₂O,m.p. 299-301° C. (decomp.)

62.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3,4-dimethoxyphehyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 153-154° C.

63.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-naphth-1-ylpiperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×3HCl×2H₂O,m.p. 206-208° C. (decomp.)

64.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-pyrimidin-2-yl-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 161-163° C.

65.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-quinolin-2-yl-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 143-145° C.

66.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methylnaphth-1-yl)-piperazin-1-yl-ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×2HCl×2H₂O,m.p. 295-297° C. (decomp.)

67.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxy-3,5-di-chlorophenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one×2HCl×H₂O,m.p. 264-267° C. (decomp.)

68.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-cyanophenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 162-164° C.

69.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-chlorphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 165-167° C.

70.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-pyridin-2-ylpiperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×3HCl×2H₂O,m.p. 232-234° C. (decomp.)

71.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-pyridin-4-ylpiperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×3HCl×2H₂O,m.p. 270-272° C. (decomp.)

72.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(5-methoxypyrimidin-4-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×3HCl×4H₂O,m.p. 266-268° C. (decomp.)

73.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-naphth-2-ylpiperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,m.p. 140-141° C.

74.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-pyrazin-2-ylpiperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×3HCl×3H₂O,m.p. 170-172° C. (decomp.)

75.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-tetralin-5-yl-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×3HCl×2H₂O,m.p. 285-287° C. (decomp.)

76.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-indan-1-ylpiperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×HCl×2H₂O,m.p. 300-301° C. (decomp.)

77.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxy-4-nitro-5-methylphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one×2HCl×2H₂O,m.p. 210-212° C. (decomp.)

78.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-isochinolin-4-yl-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×3HCl×3H₂O,m.p. 290-292° C. (decomp.)

79.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxy-4-chloro-5-methylphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×2HCl×2H₂O,m.p. 293-294° C. (decomp.)

80.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2,4-dimethoxyphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×3HCl×3H₂O,m.p. 290-291° C. (decomp.)

81.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-quinazolin-4-yl-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×3HCl×4H₂O,m.p. 258-260° C. (decomp.)

82.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3-trifluoromethyl-4-chlorophenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×2HCl×3H₂O,m.p. 311-312° C. (decomnp.)

83.3,4,5,6,7,8-Hexahydro-7-(4-chlorobenzyl)-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×3HCl×H₂O,m.p. 290-292° C. (decomp.)

84.3,4,5,6,7,8-Hexahydro-7-ethyl-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×3HCl×H₂O,m.p. 295-297° C. (decomp.)

85.3,4,5,6,7,8-Hexahydro-7-isopropyl-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×3HCl×H₂O,m.p. 300-302° C. (decomp.)

86.3,4,5,6,7,8-Hexahydro-7-(4-nitro)benzyl-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×3HCl×H₂O,m.p. 214-217° C. (decomp.)

87.3,4,5,6,7,8-Hexahydro-7-(4-methoxy)benzyl-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one×3HCl×H₂O,m.p. 278-281° C. (decomp.)

88.3,4,5,6,7,8-rHexahydro-7-(2-phenyl)ethyl-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×3HCl×H₂O,m.p. 305-306° C. (decomp.)

89.3,4,5,6,7,8-Hexahydro-7-(3-benzoyl)propyl-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one×3HCl×H₂O,m.p. 124-126° C. (decomp.)

90.3,4,5,6,7,8-Hexahydro-7-(4-amino)benzyl-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×HCl×3H₂O,m.p. 280-282° C. (decomp.)

91.3,4,5,6,7,8-Hexahydro-7-(3-phenyl)propyl-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one×2HCl×3H₂O,m.p. 301-302° C. (decomp.)

92.3,4,5,6,7,8-Hexahydro-7-(3-phenyl)propyl-3-[2-(4-naphth-1-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×2HCl×2H₂O,m.p. 306-307° C. (decomp.)

93.3,4,5,6,7,8-Hexahydro-7-(2-(4-methoxy)phenyl)ethyl-3-[2-(4-naphth-1-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×2HCl×3H₂O,m.p. 306-308° C. (decomp.)

94.3,4,5,6,7,8-Hexahydro-7-(2-(4-chloro)phenyl)ethyl-3-[2-(4-naphth-1-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×2HCl×3H₂O,m.p. 300-303° C. (decomp.)

95.3,4,5,6,7,8-Hexahydro-7-(2-phenyl)ethyl-3-[2-(4-naphth-1-yl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×2HCl×3H₂O,m.p. 295-298° C.

96.3,4,5,6,7,8-Hexahydro-7-(2-(4-hydroxy)phenyl)ethyl-3-[2-(4-naphth-1-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×2HCl×2H₂O,m.p. 254-256° C.

97.3,4,5,6,7,8-Hexahydro-7-(2-(4-chloro)phenyl)ethyl-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one×3HCl×2H₂O,m.p. 304-306° C. (decomp.)

98.3,4,5,6,7,8-Hexahydro-7-(2-naphth-1-yl)ethyl-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one×2HCl×2H₂O,m.p. 293-295° C. (decomp.)

99.3,4,5,6,7,8-Hexahydro-7-(2-benzoylamino)ethyl-3-[2-(4-naphth-1-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×2HCl×2H₂O,m.p. 292-294° C. (decomp.)

100.3,4,5,6,7,8-Hexahydro-7-(2-benzoylamino)ethyl-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one×2HCl×3H₂O,m.p. 202-204° C. (decomp.)

101.3,4,5,6,7,8-Hexahydro-7-(3-benzoylamino)propyl-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one×3HCl×2H₂O,m.p. 182-183° C. (decomp.)

102.3,4,5,6,7,8-Hexahydro-7-(3-benzoylamino)propyl-3-[2-(4-naphth-1-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×3HCl×H₂O,m.p. 128-130° C. (decomp.)

103.3,4,5,6,7,8-Hexahydro-7-(4-phenyl)butyl-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×3HCl×H₂O,m.p. 311-312° C. (decomp.)

104.3,4,5,6,7,8-Hexahydro-7-(4-phenyl)butyl-3-[2-(4-naphth-1-yl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×3HCl×H₂O,m.p. 312-314° C. (decomp.)

105.3,4,5,6,7,8-Hexahydro-7-(4-methoxy)benzyl-3-[2-(4-naphth-1-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×3HCl×H₂O,m.p. 275-277° C. (decomp.)

106.3,4,5,6,7,8-Hexahydro-7-(2-(4-methoxy)phenyl)ethyl-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×3HCl×3H₂O,m.p. 297-298° C. (decomp.)

107.3,4,5,6,7,8-Hexahydro-7-(2-phenyl)ethyl-3-[3-(4-naphth-1-yl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,m.p. 153-155° C.

108.3,4,5,6,7,8-Hexahydro-7-(2-phenyl)ethyl-3-[2-(4-pyrimidin-2-yl)piperazin-1-yl)ethyl)pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×2HCl×3H₂O,m.p. 304-305° C. (decomp.)

109.3,4,5,6,7,8-Hexahydro-7-(2-phenyl)ethyl-3-[3-(4-pyrimidin-2-yl)piperazin-1-yl)propyl)pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×3HCl×2H₂O,m.p. 302-303° C. (decomp.)

110.3,4,5,6,7,8-Hexahydro-7-(3-benzoylamino)propyl-3-[2-(4-pyrimidin-2-yl)piperazin-1-yl)ethyl)pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one×3HCl×3H₂O,m.p. 125-127° C. (decomp.)

111.3,4,5,6,7,8-Hexahydro-7-(4-phenyl)butyl-3-[2-(4-pyrimidin-2-yl)piperazin-1-yl)ethyl)pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×3HCl×3H₂O,m.p. 317-319° C. (decomp.)

112.3,4,5,6,7,8-Hexahydro-7-(2-(4-methoxy)phenyl)ethyl-3-[2-(4-pyrimidin-2-yl)piperazin-1-yl)ethylpyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one,m.p. 165-167° C.

113.3,4,5,6,7,8-Hexahydro-7-acetyl-3-[3-(4-(2-methoxyphenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-imine×2HCl,m.p. 265-268° C.

114.3,4,5,6,7,8-Hexahydro-7-acetyl-3-[3-(4-(2-methoxyphenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×2HCl×2H₂O,m.p. 264-267° C.

115.3,4,5,6,7,8-Hexahydro-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,m.p. 168-170° C.

116.3,4,5,6,7,8-Hexahydro-7-acetyl-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 170-172° C.

117.3,4,5,6,7,8-Hexahydro-7-benzoyl-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×2HCl×2H₂O,m.p. 185-187° C. (decomp.)

118.3,4,5,6,7,8-Hexahydro-7-benzoyl-3-[2-(4-naphth-1-yl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 195-197° C.

119.3,4,5,6,7,8-Hexahydro-7-benzoyl-3-[2-(4-pyrimidin-2-yl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 130-132° C. (decomp.)

120.3,4,5,6,7,8-Hexahydro-2,7-dimethyl-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one,m.p. 176-178° C.

121.3,4,5,6,7,8-Hexahydro-7-acetyl-2-hydroxy-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one,m.p. 135-137° C.

122.3,4,5,6,7,8-Hexahydro-7-methyl-3-[l-(4-(2-methoxyphenyl)-piperazin-1-yl)prop-2-yl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 184-186° C.

123.3,4,5,6,7,8-Hexahydro-3-[1-(4-naphth-1-ylpiperazin-1-yl)prop-2-yl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×2HCl×4H₂O,m.p. 242-244° C. (decomp.)

124.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×3HCl×3H₂O,m.p. 190-192° C. (decomp.)

125.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(isoquinolin-1-yl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×3HCl×3H₂O,m.p. >250° C.

126.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(6-methylpyridin-2-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 138-140° C.

127.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(4-trifluoromethyl-pyrimidin-2-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one,m.p. 291-292° C.

128.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3-trifluoromethylphenyl)-3,4-dehydropiperidin-1-yl)ethyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one,m.p. 98-100° C.

129.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3,4-dimethoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×2HCl×2H₂O,m.p. 212-214° C.

130.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3-methoxyphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,¹H NMR (CDCl₃) δ=2.5 (3H, s), 3.8 (3H, s), 7.9 (1H, s)

131.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3,5-dimethoxyphenyl]piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one,¹H NMR (CDCl₃ δ=2.5 (3H, s), 3.8 (6H, s), 6.1 (2H), 7.9 (1H, s)

132.3,4,5,6,7,8-Hexahydro-7-methyl-3-[5-(4-(3-trifluoromethyl-4-chlorophenyl)]piperazin-1-yl)pentyl]pyrido[4′,3′:4,5]-thieno-[2,3-d]pyrimidin-4-one,¹H NMR (DMSO-d₆) δ=2.5 (3H, s), 7.2 (1H, d), 8.5 (1H, s)

132.3,4,5,6,7,8-Hexahydro-7-methyl-3-[5-(4-(3-trifluoromethyl-4-chlorophenyl)piperrazin-1-yl)pentyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one,¹H NMR (DMSO-d₆) δ=2.5 (3H, s), 7.2 (1H, d), 8.5 (1H, s)

133.3,4,5,6,7,8-Hexahydro-7-methyl-3-[4-(4-naphth-1-yl-piperazin-1-yl)butyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,¹H NMR (CDCl₃) δ=2.5 (3H, s), 4.0 (2H, t), 7.1 (1H, d), 7.9 (1H, s)

134.3,4,5,6,7,8-Hexahydro-7-methyl-3-[4-(4-pyridin-2-yl-piperazin-1-yl)butyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,¹H NMR (CDCl₃) δ=2.8 (2H, t), 3.6 (2H, s), 4.0 (2H, t), 7.9 (1H, s)

135.3,4,5,6,7,8-Hexahydro-7-methyl-3-[4-(4-(6-methylpyridin-2-yl)piperazin-1-yl)butyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,¹H NMR (DMSO-d₆) δ=2.5 (3H, s), 6.8 (1H, d), 8.5 (1H, s)

136.3,4,5,6,7,8-Hexahydro-7-methyl-3-[4-(4-pyrimidin-2-yl-piperazin-1-yl)butyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,¹H NMR (DMSO-d₆) δ=2.5 (3H, s), 8.4 (1H, d), 8.5 (1H, s)

137.3,4,5,6,7,8-Hexahydro-7-methyl-3-[4-(4-phenyl-3,4-dehydropiperidin-1-yl)butyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,¹H NMR (CDCl₃) δ=2.5 (3H, s), 3.6 (2H, s), 7.9 (1H, s)

138.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(4-methylnaphth-1-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 139-141° C.

139.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3-trifluoromethylphenyl)piperidin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×2HCl×H₂O,m.p. 290-295° C.

140.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(4-fluoronaphth-1-yl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 157-158° C.

141.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(4-trifluoromethylpyridin-2-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one,m.p. 101-102° C.

142.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-pyridin-2-yl-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×HCl,¹H NMR (D₂O) δ=3.1 (3H, s), 4.4 (2H, t), 7.0 (1H, t), 8.4 (1H, s)

143.3,4,5,6,7,8-Hexahydro-7-methyl-3-[4-(4-phenylpiperidin-1-yl)butyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,¹H NMR (CDCl₃) δ=2.5 (3H, s), 4.0 (2H, t), 7.9 (1H, s)

144.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl)ethyllpyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one,m.p. 124-125° C.

145.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-phenylpiperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,m.p. 121-123° C.

146.3,4,5,6,7,8-Hexahydro-7-isopropyl-3-[2-(4-(3-trifluoromethylphenylpiperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×2HCl×H₂O,m.p. 225-227° C.

147.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(4-trifluoromethyl-6-methylpyridin-2-yl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×3HCl×2H₂O,m.p. 280-282° C.

148.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3-cyanophenylpiperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno(2,3-d]-pyrimidin-4-one×2HCl,m.p. 268-270° C.

149.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(6-trifluoromethylpyridin-2-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×2HCl,m.p. 290-292° C.

150.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(6-methylpyridin-2-yl)homopiperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×3HCl×H₂O,m.p. 212-214° C.

151.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-phenylhomopiperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×3HCl×H₂O,m.p. 222-223° C.

152.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3-trifluoromethylphenyl)homopiperazin-1-yl)ethyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one×2HCl×H₂O,m.p. >280° C.

153.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(4-methylpyrimidin-2-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 136-138° C.

154.3,4,5,6,7,8-Hexahydro-7-methyl-3-[4-(4-phenylpiperidin-1-yl)butyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=437

155.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3-phenoxyphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,ESI MS: [M+H]⁺=503

156.3,4,5,6,7,8-Hexahydro-7-ethyl-3-[2-(4-(6-methylpyridin-2-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=439

157.3,4,5,6,7,8-Hexahydro-7-(2-(3-chloro-N-benzoyl)aminoethyl)-3-[2-(4-(6-methylpyridin-2-yl)piperazin-1-yl)ethyl]-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,ESI MS: [M]⁺=592

158.3,4,5,6,7,8-Hexahydro-7-(2-nicotinamidoethyl)-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=612

159.3,4,5,6,7,8-Hexahydro-7-(2-(4-chloro-N-benzoyl)aminoethyl)-3-[2-(4-(6-methylpyridin-2-yl)piperazin-1-yl)ethyl]-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,ESI MS: [M+2H]⁺=594

160.3,4,5,6,7,8-Hexahydro-7-methyl-3-[4-(4-(3-trifluoromethylphenyl)piperazin-1-yl)butyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×2HCl,ESI MS: [M+H]⁺=520

161.3,4,5,6,7,8-Hexahydro-7-(2-(4-fluoro-N-benzoyl)aminoethyl)-3-[2-(4-(6-methylpyridin-2-yl)piperazin-1-yl)ethyl]-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,¹H NMR (270 MHz, CDCl₃): 2.4 (s, 3H), 2.6 (t, 4H), 4.1 (t, 2H), 6.4 (d,1H), 6.5 (d, 1H), 6.8 (br, 1H), 7.1 (t, 2H), 7.4 (t, 1H), 7.8 (m, 1H),8.0 (s, 1H)

162.3,4,5,6,7,8-Hexahydro-7-propyl-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one×2HCl,ESI MS: [M+H]⁺=506

163.3,4,5,6,7,8-Hexahydro-7-(4-chlorobenzyl)-3-[2-(4-(6-methylpyridin-2-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one,ESI MS: [M]⁺=535

164.3,4,5,6,7,8-Hexahydro-3-[2-(4-(6-methylpyridin-2-yl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,ESI MS; [M+H]⁺=411

165.3,4,5,6,7,8-Hexahydro-7-acetyl-3-[2-(4-(6-methylpyridin-2-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=453

166.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3-aminophenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one×HCl,ESI MS: [M+H]⁺=425

167.3,4,5,6,7,8-Hexahydro-7-(4-fluorobenzyl)-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=572

168.3,4,5,6,7,8-Hexahydro-7-(2-(4-nitro-N-benzoyl)aminoethyl)-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=656

169.3,4,5,6,7,8-Hexahydro-7-isopropyl-3-[2-(4-(6-methylpyridin-2-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=453

170.3,4,5,6,7,8-Hexahydro-7-(2-methylpropyl)-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=520

171.3,4,5,6,7,8-Hexahydro-7-(2-methylpropyl)-3-[2-(4-(6-methylpyridin-2-yl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=467

172.3,4,5,6,7,8-Hexahydro-7-propyl-3-[2-(4-(6-methylpyridin-2-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=453

173.3,4,5,6,7,8-Hexahydro-7-(2-nicotinamidoethyl)-3-[2-(4-(6-methylpyridin-2-yl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=559

174.3,4,5,6,7,8-Hexahydro-7-(2-isonicotinamidoethyl)-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,fumaric acid salt, ESI MS: [M+H]⁺=608

175.3,4,5,6,7,8-Hexahydro-7-cyclopropyl-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=504

176.3,4,5,6,7,8-Hexahydro-7-(2-phenoxyethyl)-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×HCl,ESI MS: [M+H]⁺=598

177.3,4,5,6,7,8-Hexahydro-7-(2-benzyloxyethyl)-3-[2-(4-(6-methylpyridin-2-yl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=545

178.3,4,5,6,7,8-Hexahydro-7-cyclopropyl-3-[2-(4-(6-methylpyridin-2-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one,¹H NMR (270 MHz, CDCl₃): 0.6 (s, 4H), 1.9 (p, 1H), 2.4 (s, 3H), 2.6 (t,4H), 2.7 (t, 2H), 4.1 (t, 2H), 6.4 (d, 1H), 6.5 (d, 1H), 7.4 (t, 1H),8.0 (s, 1H)

179.3,4,5,6,7,8-Hexahydro-7-methyl-3-[4-(4-(3-thiomethylphenyl)piperazin-1-yl)butyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=456

180.3,4,5,6,7,8-Hexahydro-7-(4-chlorobenzyl)-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,EI MS: [M]⁺=587

181.3,4,5,6,7,8-Hexahydro-7-(4-methoxybenzyl)-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×3HCl, EI MS: [M]⁺=583

182.3,4,5,6,7,8-Hexahydro-7-benzyl-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]-thieno[2,3-d]pyrimidin-4-one×3HCl, ESI MS: [M+H]⁺=554

183.3,4,5,6,7,8-Hexahydro-7-(2-phenylethyl)-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=568

184.3,4,5,6,7,8-Hexahydro-7-(2-(4-methoxyphenyl)ethyl)-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=598

185.3,4,5,6,7,8-Hexahydro-7-ethyl-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=492

186.3,4,5,6,7,8-Hexahydro-7-acetyl-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=506

187.3,4,5,6,7,8-Hexahydro-7-benzoyl-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=568

188.3,4,5,6,7,8-Hexahydro-7-(2-(4-chlorophenyl)ethyl)-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,ESI MS: [M]⁺=602

189.3,4,5,6,7,8-Hexahydro-7-(3-benzoylpropyl)-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×3HCl, ESI MS: [M+H]⁺=610

190.3,4,5,6,7,8-Hexahydro-7-(4-nitrobenzyl)-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=599

191.3,4,5,6,7,8-Hexahydro-7-(3-phenylpropyl)-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×3HCl, ESI MS: [M+H]⁺=582

192.3,4,5,6,7,8-Hexahydro-7-(2-benzamidoethyl)-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,¹H NMR (270 MHz, CDCl₃): 2.8-3.0 (m, 10H), 3.2 (m, 6H), 4.1 (t, 2H), 6.8(s, 1H), 7.1 (m, 3H), 7.3-7.6 (m, 4H), 7.8 (d, 2H), 8.0 (s, 1H)

193.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(3-methylphenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,ESI MS: [M+H]⁺=438

194.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(3-chlorophenyl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,ESI MS: [M]⁺=458

195.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3-methylphenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrirmidin-4-one,ESI MS: [M+H]⁺=424

196.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(2-chloro-4-trifluoromethylpyridin-6-yl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one,¹H NMR (400 MHz, CDCl₃): 2.5 (s, 3H), 2.8 (m, 4H), 3.2 (m, 2H), 3.6 (m,6H), 4.1 (t, 2H), 6.6 (s, 1H), 6.8 (s, 1H), 8.0 (s, 1H)

197.3,4,5,6,7,8-Hexahydro-7-methyl-3-[2-(4-(3-chlorophenyl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,¹H NMR (400 MHz, CDCl₃): 2.5 (s, 3H), 2.6 (t, 4H), 2.7-2.9 (m, 4H), 3.2(m, 6H), 3.6 (s, 2H), 4.1 (t, 2H), 6.7-6.9 (m, 3H), 7.2 (t, 1H), 8.0 (s,1H)

198.3,4,5,6,7,8-Hexahydro-7-methyl-3-[4-(4-(4-chlorophenyl)-piperazin-1-yl)butyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one,ESI MS: [M+H]⁺=472

199.3,4,5,6,7,8-Hexahydro-7-isopropyl-3-[2-(4-(3-trifluoromethyl-4-chlorophenyl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one×HCl,¹H NMR (400 MHz, CDCl₃): 1.1 (d, 6H), 3.1 (m, 6H), 3.8 (s, 2H), 4.1 (t,2H), 6.9 (dd, 1H), 7.1 (d, 1H), 7.3 (d, 1H), 7.9 (s, 1H)

200.3,4,5,6,7,8-Hexahydro-7-methyl-3-[4-(4-(3-trifluoromethylphenyl)piperazin-1-yl)butyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=506

201.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(3-trifluoromethylphenyl)piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one,ESI MS: [M+H]⁺=492

202.3,4,5,6,7,8-Hexahydro-7-methyl-3-[3-(4-(isoquinolin-1-yl)-piperazin-1-yl)propyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one

203.3,4,5,6,7,8-Hexahydro-7-methyl-3-[4-(4-(isoquinolin-1-yl)-piperazin-1-yl)butyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one

204.3,4,5,6,7,8-Hexahydro-3-[2-(4-(isoquinolin-1-yl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one

205.3,4,5,6,7,8-Hexahydro-7-acetyl-3-[2-(4-(isoquinolin-1-yl)-piperazin-1-yl)ethyl]pyrido[4′,3′;4,5]thieno[2,3-d]-pyrimidin-4-one

206.3,4,5,6,7,8-Hexahydro-7-ethyl-3-[2-(4-(isoquinolin-1-yl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one

207.3,4,5,6,7,8-Hexahydro-7-propyl-3-[2-(4-(isoquinolin-1-yl)-piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-4-one

208.3,4,5,6,7,8-Hexahydro-7-cyclopropyl-3-[2-(4-(isoquinolin-1-yl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one

209.3,4,5,6,7,8-Hexahydro-7-cyclopropylmethyl-3-[2-(4-(isoquinolin-1-yl)piperazin-1-yl)ethyl]pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one

These compounds are suitable for treating central nervous system-relatedemotional disturbances such as seasonal affective disturbances anddysthymia. These disturbances also include anxiety states such asgeneralized anxiety, panic attacks, sociophobia, obsessional neurosesand post-traumatic stress symptoms, disturbances of the memory,including dementia, amnesias and age-related loss of memory, and alsopsychogenic eating disturbances such as anorexia nervosa and bulimianervosa.

DE 1973444.5 describes 3-substituted3,4,5,7-tetrahydropyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine derivativesof the formula I

where

R¹ is hydrogen, a C₁-C₄-alkyl group, an acetyl group, a phenylalkylC₁-C₄ radical, with the aromatic moiety optionally being substituted byhalogen, or C₁-C₄-alkyl, trifluoromethyl, hydroxyl, C₁-C₄-alkoxy, amino,cyano or nitro groups, or a carboxylic-C₁-C₃-alkyl ester radical,

R² is a phenyl, pyridyl, pyrimidinyl or pyrazinyl group which isoptionally monosubstituted or disubstituted by halogen atoms,C₁-C₄-alkyl, or trifluoromethyl, trifluoromethoxy, hydroxyl,C₁-C₄-alkoxy, amino, monomethylamino, dimethylamino, cyano or nitrogroups, and which can optionally be fused to a benzene nucleus which canoptionally be monosubstituted or disubstituted by halogen atoms, orC₁-C₄-alkyl, hydroxy, trifluoromethyl, C₁-C₄-alkoxy, amino, cyano ornitro groups, and which can optionally contain 1 nitrogen atom, or to a5- or 6-membered ring which can contain 1-2 oxygen atoms,

A is NH or oxygen,

Y is CH₂, CH₂—CH₂, CH₂—CH₂—CH₂ or CH₂—CH,

Z is nitrogen, carbon or CH, with it also being possible for the bondbetween Y and Z to be a double bond,

and n is the number 2, 3 or 4.

These compounds of the formula I can be prepared by reacting a compoundof the formula II

in which R¹ has the abovementioned meanings, R³ is a cyano group or aC₁₋₃-alkyl-carboxylic ester group, and R⁴ is C₁₋₃-alkyl, with a primaryamine of the formula III

where R² has the abovementioned meanings, and optionally converting theresulting compound into the acid addition salt of a physiologicallytolerated acid.

The reaction expediently takes place in an inert organic solvent, inparticular a lower alcohol, e.g. methanol or ethanol, or a cyclic,saturated ether, in particular tetrahydrofuran or dioxane.

As a rule, the reaction takes place at from 20 to 110° C., in particularfrom 60 to 90° C., and has generally finished within from 1 to 10 hours.

Or, a compound of the formula II

in which R¹ has the abovementioned meanings, R³ is a cyano group or aC₁₋₃-alkyl-carboxylic ester group, and R⁴ is C₁₋₃-alkyl, is reacted witha primary aminoalcohol of the formula IV

in an inert solvent, preferably alcohols such as ethanol, at from 60° to120° C., to give the cyclization product V (X=OH)

which is then converted into the corresponding halogen derivative V(X=Cl, Br) using a halogenating agent, such as thionyl chloride orhydrobromic acid, in an organic solvent, such as a halogenohydrocarbon,or without any solvent, at from room temperature to 100° C. Finally, thehalogen derivative of the formula V (X=Cl, Br) is reacted with an amineof the formula VI

where Y, Z and R² have the abovementioned meanings, to give the novelend product of the formula I. This reaction proceeds most efficiently inan inert organic solvent, preferably toluene or xylene, in the presenceof a base, such as potassium carbonate or potassium hydroxide, at from60° C. to 150° C.

The novel compounds of the formula I can be purified either byrecrystallization from the customary organic solvents, preferably from alower alcohol, such as ethanol, or by means of column chromatography.

The free 3-substituted3,4,5,7-tetrahydropyrrolo[3′,4′:4,5]-thieno[2,3-d]pyrimidine derivativesof the formula I can be converted in the customary manner into the acidaddition salts of a solution using the stoichiometric quantity of thecorresponding acid. Examples of pharmaceutically tolerated acids arehydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid,amidosulfonic acid, maleic acid, fumaric acid, oxalic acid, tartaricacid and citric acid.

The following Examples serve to clarify the invention:

A Preparation of the starting materials

a) 2-Amino-3,5-dicarboethoxy-4,6-dihydrothieno[3,2-c]pyrrole

16.1 ml (150 mmol) of ethyl cyanoacetate and 4.8 g (150 mmol) ofpowdered sulfur were added to 23.6 g (150 mmol) of ethylpyrrolidin-3-one-1-carboxylate (Kuhn, Osswald: Chem. Ber. 89, 1435(1956)) in 60 ml of ethanol, after which 15.6 ml (112 mmol) oftriethylamine were added dropwise under a nitrogen atmosphere and whilestirring thoroughly. The mixture was then left to stir overnight at roomtemperature. After the mixture had been evaporated, the residue wasdissolved in 70 ml of ethyl acetate and the solution was left tocrystallize while stirring. After cooling, the crystals were filteredoff with suction while being rewashed with a small quantity of coldethyl acetate. 13.2 g (31%) of product having a m.p. of 154-156° C. wereisolated.

b)2-Ethoxymethyleneamino-3,5-dicarboethoxy-4,6-dihydrothieno-[3,2-c]pyrrole

0.3 ml of acetic anhydride was added to 1.4 g (4.8 mmol) of2-amino-3,5-dicarboethoxy-4,6-dihydrothieno[3,2-c]pyrrole in 14 ml oftriethyl orthoformate, and the mixture was boiled under nitrogen and atreflux for 1 h. After that, the mixture was evaporated right down at 80°C. on a rotary evaporator. 1.6 g (99%) of crude product were isolated asa viscous oil, which is sufficiently pure for further reaction.

c)3-(2-Hydroxyethyl)-6-carboethoxy-3,4,5,7-tetrahydropyrrolo-[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one

13 ml (215 mmol) of ethanolamine were added to 15.5 g (46 mmol) of2-ethoxymethyleneamino-3-carboethoxy-5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridinein 250 ml of ethanol, and the mixture was boiled at reflux for 3 h. Itwas then left to cool down and was stirred thoroughly in an icebath. Thefine solids which had precipitated out were filtered off with suctionand rewashed with cold ethyl acetate. 5.5 g (36%) of a pale brownproduct were isolated. M.p. 243-245° C.

d)3-(2-Chloroethyl)-6-carboethoxy-3,4,5,7-tetrahydropyrrolo-[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one

5.5 g (17.8 mmol) of3-(2-hydroxyethyl)-6-ethyl-3,4,5,6,7,8-hexahydropyrido[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-onein 50 ml of 1,2-dichloroethane were heated to reflux (slow dissolution),after which 2 ml (27 mmol) of thionyl chloride in 10 ml of1,2-dichloroethane were added dropwise. After 1 h of reflux boiling, thereaction mixture was evaporated, after which the residue was stirredthoroughly in a little dichloromethane and the solids were filtered offwith suction. 5.4 g (92%) of product were isolated, with this productbeing sufficiently pure for the subsequent reactions, m.p. 169-171° C.

e) N-(1-Naphthyl)piperazine

83.2 g (966 mmol) of piperazine, 38.0 g (339 mmol) of potassiumtert-butoxide and 50.0 g (241 mmol) of 1-bromonaphthalene were added toa mixture of 5,4 g (24.2 mmol) of palladium acetate and 14.7 g (48.3mmol) of tri-o-tolylphosphipe in 500 ml of xylene, and the reactionmixture was heated at reflux for 10 h, while stirring thoroughly andunder a nitrogen atmosphere. After that, the mixture was diluted withmethylene chloride, the insoluble residues were filtered off and thefiltrate was evaporated. The crude product was purified by columnchromatography (silica gel, eluent THF/methanol/ammonia 85/13/2). 21.5 g(42%) of product having a m.p. of 84-86° C. were isolated.

f) N-(2-Methyl-1-naphthyl)piperazine

14.7 g (82.7 mmol) of bis(2-chloroethyl)amine×HCl were added to 13.0 g(82.7 mmol) of 1-amino-2-methylnaphthalene in 100 ml of chlorobenzene,and the mixture was boiled under nitrogen and at reflux for 90 h. Themixture was then evaporated and the residue was partitioned betweenmethylene chloride and water at pH=9; the organic phase was thenevaporated after having been dried. The crude product was purified bycolumn chromatography (silica gel, eluent THF/methanol/ammonia 85/13/2).11.6 g (62%) of product were isolated.

g) 4-Piperazin-1-ylisoquinoline

4.51 g (21.7 mmol) of 4-bromoisoquinoline, 4.65 g (25.0 mmol) of t-butylpiperazine-N-carboxylate, 0.1 g (0.11 mmol) oftris(dibenzylideneacetone)dipalladium, 0.11 g (0.18 mmol) of2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 2.92 g (30.4 mmol) ofsodium tert-butoxide were together added to 50 ml of toluene, and themixture was stirred at 75° C. for 2 h. The reaction mixture was added toice/sodium chloride, and this latter mixture was then extracted withethyl acetate, after which the organic phase was dried over sodiumsulfate and the solvent was removed on a rotary evaporator. The productcrystallized out and was then filtered off with suction and washed withpentane. 5.5 g (81%) of the Boc-protected piperazine were obtained(m.p.; 111° C.). 5.2 g (16.6 mmol) of this substance were taken up in 17ml of dichloromethane, after which 17 ml (0.22 mmol) of trifluoroaceticacid were added slowly to this solution at 0° C. The mixture was left tostir at 0° C. for 4 h, after which it was poured onto ice water and thislatter mixture was then extracted with dichloromethane. The aqueousphase was filtered, rendered alkaline and then extracted withdichloromethane. After having dried over sodium sulfate, and to a largeextent removed the solvent, dilution took place with diethyl ether andthe hydrochloride was precipitated with ethereal hydrochloric acid. Thisresulted in 3.2 g (67%) of the product, having a m.p. of 293-294° C.

Insofar as they were not known from the literature (cf. PatentApplication DE 19636769.7 as well), additional piperazine derivatives(see Examples) were prepared in analogy with e), f) and g).

B Preparation of the end products

EXAMPLE 13,4,5,7-Tetrahydro-6-carboethoxy-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one

1.1 g (4.8 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)-piperazine wereadded to 1.6 g (4.8 mmol) of2-ethoxymethylene-amino-3,5-dicarboethoxy-4,6-dihydrothieno-[3,2-c]pyrrolein 25 ml of ethanol, and the mixture was boiled at reflux for 2 h. Afterthat, the mixture was evaporated on a rotary evaporator and the crudeproduct was purified by column chromatography (silica gel, eluentmethylene chloride/methanol 96/4). 1.1 g (47%) of product, having a m.p.of 153-155° C., were isolated after recrystallization from ethylacetate.

EXAMPLE 2

0.7 g (3.0 mmol) of N-(1-naphthyl)homopiperazine and 0.5 g (3.6 mmol) offinely powdered potassium carbonate were added to 1.0 g (3.0 mmol) of3-(2-chloroethyl)-6-carboethoxy-3,4,5,7-tetrahydropyrrolo[3′,4′:4,5]thieno[2,3d]pyrimidin-4-onein 40 ml of xylene, and the mixture was boiled under a nitrogenatmosphere and at reflux for a total of 70 h. The mixture was thenevaporated in vacuo and the residue was partitioned at pH=10 betweenmethylene chloride and water. After the organic phase had been dried andevaporated, the crude produce was purified by means of MPLC (eluentmethanol/dichloromethane). 0.6 g (38% of hydrochloride, having a m.p. of160° C. (decom.), was isolated by precipitation with etherealhydrochloric acid from a solution of the product in acetone.

EXAMPLE 33,4,5,7-Tetrahydro-3-[2-(4-(1-naphthyl)piperazin-1-yl)ethyl]-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one×2HCl×2 H₂O

9.4 g (18.7 mmol) of3,4,5,7-tetrahydro-6-carboethoxy-3-[2-(4-(1-naphthyl)piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]-thieno[2,3-d]pyrimidin-4-onewere introduced into a mixture of 80 ml of conc. hydrochloric acid and80 ml of water and the whole was then boiled at reflux for 7 h. Thereaction mixture was poured onto ice water and the resulting mixture wasadjusted to pH=10 with conc. sodium hydroxide solution and extractedtwice with methylene chloride. After having dried and evaporated theorganic phase, the crude product was purified by column chromatography(silica gel, eluent methylene chloride/methanol 90/10). This resulted inthe isolation of 2.4 g (30%) of product, which was dissolved in ethylacetate and converted into the hydrochloride having a m.p. of 288-290°C. (decomp.).

EXAMPLE 43,4,5,7-Tetrahydro-6-ethyl-3-[2-(4-(1-naphthyl)piperazin-1-yl)-ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one×2HCl×3 H₂O

0.68 ml (8.5 mmol) of iodoethane and 0.5 g (3.5 mmol) of finely powderedpotassium carbonate were added to 1.5 g (3.5 mmol) of3,4,5,7-tetrahydro-3-[2-(4-(1-naphthyl)piperazin-1-yl)ethyl]-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one in 30 ml oftetrahydrofuran, and the mixture was boiled at reflux for 3 h. Themixture was then poured onto ice/water and this resulting mixture wasadjusted to pH=9 with ammonia and extracted twice with methylenechloride. After the organic phase had been dried and evaporated, thecrude product was purified by column chromatography (silica gel, eluentmethylene chloride/methanol 95/5). This resulted in the isolation of 0.4g (25%) of product, which was dissolved in ethyl acetate and convertedinto the hydrochloride having a m.p. of 202-204° C. (decomp.).

EXAMPLE 53,4,5,7-Tetrahydro-6-acetyl-3-[2-(4-(1-naphthyl)piperazin-1-yl)-ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-oneEXAMPLE 63,4,5,7-Tetrahydro-6-benzyl-3-[2-(4-(1-naphthyl)piperazin-1-yl)-ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-oneEXAMPLE 73,4,5,7-Tetrahydro-6-(4-chlorophenyl-2-ethyl)-3-[2-(4-(1-naphthyl)piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

The following can be prepared in analogy with Examples 1 to 7:

8.3,4,5,7-Tetrahydro-6-carboethoxy-3-[2-(4-(1-naphthyl)-piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 190-192° C.

9.3,4,5,7-Tetrahydro-6-carboethoxy-3-[2-(4-(2-methyl-1-naphthyl)piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]-thieno[2,3-d]pyrimidin-4-one

10.3,4,5,7-Tetrahydro-6-carboethoxy-3-[2-(4-(2-methoxy-1-napthyl)piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]-thieno[2,3-d]pyrimidin-4-one

11.3,4,5,7-Tetrahydro-6-carboethoxy-3-[2-(4-pyrimidin-2-yl-piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 166° C.

12.3,4,5,7-Tetrahydro-6-carboethoxy-3-[2-(4-(2-methoxyphenyl)-piperidin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

13.3,4,5,7-Tetrahydro-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

14.3,4,5,7-Tetrahydro-3-[2-(4-naphth-1-ylhexahydro-1,4-diazepin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

15.3,4,5,7-Tetrahydro-3-[2-(4-(2-methylphenyl)-piperazin-1-yl)-ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one

16.3,4,5,7-Tetrahydro-3-[2-(4-tetralin-5-yl-piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]-thieno[2,3-d]pyrimidin-4-one

17.3,4,5,7-Tetrahydro-3-[2-(4-indan-1-ylpiperazin-1-yl)ethyl]-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one

18.3,4,5,7-Tetrahydro-3-[2-(4-(2-methoxyphenyl)-3,4-dehydropiperidin-1-yl)ethyl]pyrrolo[3′,4′:4,5]-thieno[2,3-d]pyrimidin-4-one

19.3,4,5,7-Tetrahydro-3-[2-(4-naphth-1-ylpiperidin-1-yl)ethyl]-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one

20.3,4,5,7-Tetrahydro-3-[2-(4-(2-methoxynaphth-1-yl-3,4-dehydropiperidin-1-yl)ethyl]pyrrolo[3′,4′:4,5]-thieno[2,3-d]pyrimidin-4-one

21.3,4,5,7-Tetrahydro-6-ethyl-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one

22.3,4,5,7-Tetrahydro-6-ethyl-3-[2-(4-(2,3-dimethylphenyl)-piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one

23.3,4,5,7-Tetrahydro-6-ethyl-3-[2-(4-(2-chlorophenyl)-piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one

24.3,4,5,7-Tetrahydro-6-ethyl-3-[2-(4-pyrimidin-2-yl-piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

25.3,4,5,7-Tetrahydro-6-ethyl-3-[2-(4-pyridin-2-yl-piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

26.3,4,5,7-Tetrahydro-6-ethyl-3-[2-(4-quinolin-2-yl-piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

27.3,4,5,7-Tetrahydro-6-ethyl-3-[2-(4-(2-methoxyphenyl)-piperidin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one

28.3,4,5,7-Tetrahydro-6-ethyl-3-[3-(4-pyrimidin-2-yl-piperazin-1-yl)propyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

29.3,4,5,7-Tetrahydro-6-methyl-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one

30.3,4,5,7-Tetrahydro-6-methyl-3-[2-(4-(2-cyanophenyl)-piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one

31.3,4,5,7-Tetrahydro-6-methyl-3-[2-(4-isoquinolin-4-yl-piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one

32.3,4,5,7-Tetrahydro-6-methyl-3-[2-(4-naphth-1-yl-3,4-dehydropiperidin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one

33.3,4,5,7-Tetrahydro-6-acetyl-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

34.3,4,5,7-Tetrahydro-6-acetyl-3-[2-(4-(2-methyl-1-naphthyl)-piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one

35.3,4,5,7-Tetrahydro-6-benzyl-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one

36.3,4,5,7-Tetrahydro-6-(4-nitrophenyl-2-ethyl)-3-[2-(4-(1-naphthyl)piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one

37.3,4,5,7-Tetrahydro-6-(4-aminobenzyl)-3-[2-(4-(2-methyl-1-naphthyl)piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one

38.3,4,5,7-Tetrahydro-6-carboethoxy-3-[2-(4-(2-methylphenyl)-piperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one,m.p. 152° C.

39.3,4,5,7-Tetrahydro-6-carboethoxy-3-[2-(4-(2-chlorophenyl)-piperazin-1-yl)propyl]pyrrolo[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one,m.p. 172° C.

40.3,4,5,7-Tetrahydro-6-carboethoxy-3-[2-(4-(2-phenylpiperidin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

41.3,4,5,7-Tetrahydro-6-carboethoxy-3-[2-(4-(2-naphth-1-yl-piperidin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

42.3,4,5,7-Tetrahydro-6-carboethoxy-3-[2-(4-(2-naphth-1-yl-3,4-dehydropiperidin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

43.3,4,5,7-Tetrahydro-6-carboethoxy-3-[3-(4-(2-cyanophenyl)-piperazin-1-yl)propyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 190° C.

44.3,4,5,7-Tetrahydro-6-carboethoxy-3-[2-(4-indan-4-ylpiperazin-1-yl)ethyl]pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one,m.p. 149° C.

C Measuring receptor binding

Preparing the receptor-bearing cell membranes

The receptor binding studies were carried out using “membranepreparations” which were obtained from cell cultures of the humanembryonic kidney cell line 293 (HEK 293) into which a specific serotoninreceptor subtype (h5HT1A, h5HT1B or h5HT1D) has in each case been clonedand in which this subtype is permanently expressed.

The cells were grown in RPMI 1640 medium (Life Technologies), whichadditionally contained 10% fetal calf serum (FCS), 2 mmol ofL-glutamine/l and 400 mg of geneticin G 418/l . The cells were incubatedin so-called “tank stacks”, at 37° C. in an incubator gassed with air/5%CO₂, until they had reached a confluent monolayer. The cells were thendetached from the culture vessels using a buffer of the followingcomposition: (values per liter) trypsin, 10 mg; EDTA, 4 mg; EGTA, 200mg; KCl, 200 mg; KH₂PO₄, 200 mg; Na₂HPO₄, 1.15 g; NaCl, 8.0 g; pH 7.4.The cell suspension was pelleted and then resuspended in Dulbecco'sphosphate-buffered saline (PBS); the cell density was then adjusted toapprox. 10⁸ cells/ml. After the cells had been pelleted once again, thePBS was replaced by the same volume of ice-cold lysis buffer (5 mmol oftris/l; 10% glyzerol; pH 7.4) and the cells were incubated at 4° C. for30 min. The lyzed cells (=“membranes”) were aliquoted and stored inliquid nitrogen until used in receptor binding studies. An aliquot wasused per preparation for determining the protein content.

The novel compounds display a high affinity (K; ≦30 nM) for human5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) receptor types, which are expressedin cloned cell lines.

Receptor binding assay

The receptor binding studies were carried out in 1 ml Macrowell tubeswhich contained the following components:

50 μl of the test substance at differing concentrations for competitionmeasurements or 50 μl of assay buffer or 50 μl of unlabeled serotonin (1μmol/l final volume) for determining the total or non-specific bindingcontrol

200 μl of suspension of membranes of the appropriate receptor subtypehaving a protein content of 200 μg/tube

250 μl of radioligand solution ([³H]5-carboxamidotryptamine (5-CT) forthe h5HT1B and h5RT1D receptors or [³H]8-hydroxydipropylaminotetralin(8-OH-DPAT) for the h5HT1A receptors. The final concentrations of theradioligands were adjusted to 3 nmol/l or 0.3 nmol/l.

The assay buffer (pH 7.4) had the following composition (per liter):tris, 6.057 g; CaCl₂x2H₂O=5.88 g; ascorbic acid, 1 g; pargyline, 1.96mg.

The assay mixture was incubated at 25° C. for 30 min and then filteredthrough a fiberglass filter (Whatman GF/B) using a cell harvestingappliance (Skatron), with the filters then being washed with from 5 to 9ml of cold buffer. The filters were in each case placed, together with 5ml of Ultima GoldxR liquid scintillator (Packard), in scintillationvials, which were shaken for 1 hour. The radioactivity was thendetermined in a beta counter (Wallac). The measurement data wereevaluated by an iterative non-linear regression analysis using the“Statistical Analysis System (SAS)” which is similar-to the “LIGAND”program described by Munson and Rodbard (Anal. Biochem: 107, 220(1980)). The competition constants (K_(i)) were recorded in nmol/l.

These compounds are suitable for treating central nervous system-relatedemotional disturbances such as seasonal affective disturbances anddysthymia. These disturbances also include anxiety states such asgeneralized anxiety, panic attacks, sociophobia, obsessional neurosesand post-traumatic stress symptoms, disturbances of the memory,including dementia, amnesias and age-related loss of memory, and alsopsychogenic eating disturbances such as anorexia nervosa and bulimianervosa.

DE 19724980.9 describes 3-substituted3,4-dihydrothieno-[2,3-d]pyrimidine derivatives of the formula I

where

R¹ and R² are hydrogen or a C₁-C₄-alkyl group,

R³ is a phenyl, pyridyl, pyrimidinyl or pyrazinyl group which isoptionally monosubstituted or disubstituted by halogen atoms,C₁-C₄-alkyl, or trifluoromethylt trifluoromethoxy, hydroxy,C₁-C₄-alkoxy, amino, monomethylamino, dimethylamino, cyano or nitrogroups, and which can optionally be fused to a benzene nucleus which canoptionally be monosubstituted or disubstituted by halogen atoms, orC₁-C₄-alkyl, hydroxy, trifluoromethyl, C₁-C₄-alkoxy, amino, cyano ornitro groups and which can optionally contain 1 nitrogen atom, or to a5- or ⁶-membered ring which can contain 1-2 oxygen atoms,

A is NH or oxygen,

Y is CH₂, CH₂—CH₂, CH₂—CH₂—CH₂ or CH₂—CH,

Z is nitrogen, carbon or CH, with it also being possible for the bondbetween Y and Z to be a double bond,

and n is the number 2, 3 or 4.

These compounds of the formula I can be prepared by reacting a compoundof the formula II

in which R¹ has the abovementioned meanings, R³ is a cyano group or aC₁₋₃-alkyl-carboxylic ester group, and R⁴ is C₁₋₃-alkyl, with a primaryamine of the formula III

where R³ has the abovementioned meanings, and optionally converting theresulting compound into the acid addition salt of a physiologicallytolerated acid.

The reaction expediently takes place in an inert organic solvent, inparticular a lower alcohol, e.g. methanol or ethanol, or a cyclic,saturated ether, in particular tetrahydrofuran or dioxane.

As a rule, the reaction takes place at from 20 to 110° C., in particularat from 60 to 90° C., and has generally finished within from 1 to 10hours.

Or, a compound of the formula II

where R¹ has the abovementioned meaning, R³ is a cyano group or aC₁₋₃-alkyl-carboxylic ester group, and R⁴ is C₁₋₃-alkyl, is reacted witha primary aminoalcohol of the formula IV

an inert solvent, preferably alcohols such as ethanol, at from 60° to120° C., in order to give the cyclization product V (X=OH)

which is subsequently converted into the corresponding halogenderivative V (X=Cl, Br) using a halogenating agent such as thionylchloride or hydrobromic acid, in an organic solvent such as ahalogenohydrocarbon, or without any solvent, at from room temperature to100° C. Finally, the halogen derivative of the formula V (X=Cl, Br) isreacted with an amine of the formula VI

where Y, Z and R² have the abovementioned meanings, to give the novelend product of the formula I. This reaction proceeds most efficiently inan inert organic solvent, preferably toluene or xylene, in the presenceof a base, such as potassium carbonate or potassium hydroxide, at from60° C. to 150° C.

The novel compounds of the formula I can be purified either byrecrystallization from the customary organic solvents, preferably from alower alcohol, such as ethanol, or by means of column chromatography.

The free 3-substituted pyrido[3′,4′:4,5]thieno[2,3-d]-pyrimidinederivatives of the formula I can be converted, in the customary manner,into the acid addition salts of a solution using the stoichiometricquantity of the corresponding acid. Examples of pharmaceuticallytolerated acids are hydrochloric acid, phosphoric acid, sulfuric acid,methanesulfonic acid, amidosulfuric acid, maleic acid, fumaric acid,oxalic acid, tartaric acid and citric acid.

The following Examples serve to clarify the invention:

A Preparation of the starting materials

a) 2-Amino-3-carboethoxy-5-methyl-5-dimethylcarbamoylthiophene

82.8 ml (775 mmol) of ethyl cyanoacetate and 24.8 g (755 mmol) ofpowdered sulfur were added to 100 g (775 mmol) of dimethylacetoacetamidein 400 ml of ethanol, and, after that, 90 ml (647 mmol) of triethylaminewere added dropwise under a nitrogen atmosphere and while stirringthoroughly. After 1 h, the mixture was heated to reflux for 8 h and wasthen subsequently left to stir overnight at room temperature. Themixture was evaporated under reduced pressure and the residue was takenup in 2 l of water; this solution was adjusted to pH=9 and extractedtwice with methylene chloride. After the organic phase had been driedand evaporated, the crude product (70 g) was purified by dissolving itin 200 ml of boiling ethyl acetate. The solids which had precipitatedout overnight in association with stirring were filtered off withsuction, after cooling in an icebath, and rewashed several times withcold ethyl acetate. 39.0 g (20%) of product were isolated as gray solidshaving a m.p. of 122-124° C.

b)2-Ethoxymethyleneamino-3-carboethoxy-4-methyl-5-dimethylcarbamoylthiophene

2.0 ml of acetic anhydride were added to 30.6 g (119 mmol) of2-amino-3-carboethoxy-4-methyl-5-dimethylcarbamoyl-thiophene in 150 mlof triethyl orthoformate, and the mixture was boiled under nitrogen andat reflux for 2 h. The mixture was then evaporated right down at 80° C.on a rotary evaporator. 35.6 g (96%) of crude product were isolated as adark oil, which is sufficiently pure for further reaction.

c)3-(2-Hydroxyethyl)-5-methyl-6-dimethylcarbamoylthieno[2,3-d]-pyrimidin-4-one

8.0 ml (133 mmol) of ethanolamine were added to 35.6 g (114 mmol) of2-ethoxymethyleneamino-3-carboethoxy-5-methyl-5-dimethylcarbamoylthiophenein 200 ml of ethanol, and the mixture was boiled at reflux for 2 h. Themixture was then evaporated under reduced pressure. 29.9 g (93%) of adark viscous oil were isolated.

d)3-(2-Chloroethyl)-5-methyl-6-dimethylcarbamoylthieno[2,3-d]-pyrimidin-4-one

29.9 g (106 mmol) of3-(2-hydroxyethyl)-5-methyl-6-dimethylcarbamoylthieno[2,3-d]pyrimidin-4-onein 200 ml of 1,2-dichloroethane were heated to reflux (slowdissolution), after which 12.7 ml (175 mmol) of thionyl chloride in 20ml of 1,2-dichloroethane were added dropwise. After 1 h of refluxboiling, the reaction mixture was evaporated after it had been cooleddown. The crude product was partitioned between methylene chloride andwater at pH=9. After the organic phase had been dried and evaporated,44.1 g (83%) of product were isolated as a dark oil, which was purifiedby column chromatography (silica gel, eluent ethyl acetate). 23.8 g(76%) of product, having a m.p. of 120-122° C., were isolated.

Other C₁-C₄-mono- or dialkyl-carbamoyl derivatives of the formulae IIand V can be prepared in analogy with the directions given in a) to d).

e) N-(1-Naphthyl)piperazine

83.2 g (966 mmol) of piperazine, 38.0 g (339 mmol) of potassiumtert-butoxide and 50.0 g (241 mmol) of 1-bromonaphthalene were added toa mixture of 5.4 g (24.2 mmol) of palladium acetate and 14.7 g (48.3mmol) of tri-o-tolylphosphine in 500 ml of xylene, and the reactionmixture was heated at reflux for 10 h under a nitrogen atmosphere andwhile stirring thoroughly. After that, the mixture was diluted withmethylene chloride, the insoluble residues were filtered off and thefiltrate was evaporated. The crude product was purified by columnchromatography (silica gel, eluent THF/methanol/ammonia 85/13/2). 21.5 g(42%) of product having a m.p. of 84-86° C., were isolated.

f) N-(2-Methyl-1-naphthyl)piperazine

14.7 g (82.7 mmol) of bis(2-chloroethyl)amine×HCl were added to 13.0 g(82.7 mmol) of 1-amino-2-methylnaphthalene in 100 ml of chlorobenzene,and the mixture was boiled under nitrogen and at reflux for 90 h. Themixture was then evaporated and the residue was partitioned betweenmethylene chloride and water at pH=9; the organic phase was thenevaporated after having been dried. The crude product was purified bycolumn chromatography (silica gel, eluent THF/methanol/ammonia 85/13/2).11.6 g (62%) of product were isolated.

g) 4-Piperazin-1-ylisoquinoline

4.51 g (21.7 mmol) of 4-bromoisoquinoline, 4.65 g (25.0 mmol) oftert-butyl piperazine-N-carboxylate, 0.1 g (0.11 mmol) oftris(dibenzylideneacetone)dipalladium, 0.11 g (0.18 mmol) of2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 2.92 g (30.4 mmol) ofsodium tert-butoxide were together added to 50 ml of toluene and themixture was stirred at 75° C. for 2 h. The reaction mixture was thenadded to ice/sodium chloride and this latter mixture was then extractedwith ethyl acetate; the organic phase was then dried over sodium sulfateand the solvent was removed on a rotary evaporator. The productcrystallized out and was filtered off with suction and washed withpentane. 5.5 g (81%) of the Boc-protected piperazine were obtained(m.p.: 111° C.). 5.2 g (16.6 mmol) of this substance were taken up in 17ml of dichloromethane, and 17 ml (0.22 mmol) of trifluoroacetic acidwere added slowly at 0° C. The mixture was left to stir at 0° C. for 4h, after which it was poured onto ice water and the resulting mixturewas extracted with dichloromethane. The aqueous phase was filtered,rendered alkaline and extracted with dichloromethane. After having driedover sodium sulfate and to a large extent having removed the solvent,dilution was effected with diethyl ether and the hydrochloride wasprecipitated with ethereal hydrochloric acid. This resulted in 3.2 g(67%) of the product having a m.p. of 293-294° C.

Insofar as they were not known from the literature (cf. PatentApplication DE 19636769.7 as well), additional piperazine derivatives(see Examples) were prepared in analogy with e), f) and g).

B Preparation of the end products

EXAMPLE 13,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one

1.9 g (8.0 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine wereadded to 2.4 g (7.8 mmol) of2-ethoxymethyleneamino-3-carboethoxy-4-methyl-5-dimethylcarbamoylthiophenein 30 ml of ethanol, and the mixture was boiled at reflux for 2 h. Afterstanding overnight, the product crystallized out and was filtered offwith suction and washed with a little ethanol. 2.2 g (62%) of product,having a m.p. of 188-190° C., were isolated.

EXAMPLE 23,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2,3-dimethyl-phenyl)piperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one

1.1 g (5.0 mmol) of 1-(2,3-dimethylphenyl)piperazine hydrochloride and1.54 ml (11 mmol) of triethylamine were added to 1.5 g (5.0 mmol) of3-(2-chloroethyl)-5-methyl-6-dimethylcarbamoylthieno[2,3-d]pyrimidin-4-onein 15 ml of dimethylformamide, and the mixture was heated, at 125° C.and under nitrogen, for a total of 3 h. After the mixture had beenpoured into water, the resulting mixture was extracted with ethylacetate, after which the organic phase was extracted at pH=2 with dilutehydrochloric acid; the aqueous phase which resulted from this wasrendered basic with dilute sodium hydroxide solution. The crude productwas extracted with dichloromethane, after which drying took place oversodium sulfate and the solvent was removed under reduced pressure. Theoily residue was crystallized from a little methanol and filtered offwith suction. This resulted in 0.7 g (31%) of product having a m.p. of160-161° C.

The following were prepared in analogy with Examples 1 and 2:

3.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(1-naphthyl)piperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one,m.p. 190-191° C.

4.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-methyl-1-naphthyl)piperazin-1-yl)ethyl]-thieno[2,3-d]pyrimidin-4-one,m.p. 178-180° C.

5.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-methoxy-1-naphthyl)piperazin-1-yl)ethyl]-thieno[2,3-d]pyrimidin-4-one×H₂O,m.p. 153-155° C. (decomp.)

6.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-methylphenyl)piperazin-1-yl)ethyl]-thieno[2,3-d]pyrimidin-4-one

7.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]thieno[2,3-d]-pyrimidin-4-one,m.p. 146° C.

8.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-chlorophenyl)piperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one

9.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-pyrimidin-2-ylpiperazin-1-yl)ethyl]thieno-[2,3-d]pyrimidin-4-one×2HCl×4H₂O, m.p. 180-182° C. (decomp.)

10.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-pyridin-2-ylpiperazin-1-yl) ethyl] thieno[ 2, 3-d]pyriidin-4-one

11.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-quinolin-2-ylpiperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one

12.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(3,5-dichlorophenyl)piperazin-1-yl)ethyl]thieno[2,3-d]-pyrimidin-4-one

13.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-tetralin-5-ylpiperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one,m.p. 174° C.

14.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-indan-4-ylpiperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one,m.p. 153° C.

15.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-cyanophenyl)piperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one,m.p. 210° C. (hydrochloride)

16.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-isoquinolin-4-ylpiperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one

17.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[3-(4-pyrimidin-2-ylpiperazin-1-yl)propyl]thieno[2,3-d]pyrimidin-4-one×2HCl×2 H₂O, m.p. 209-211° C. (decomp.)

18.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-methoxyphenyl)piperidin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one

19.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-methoxyphenyl)-3,4-dihydropiperidin-1-yl)ethyl]thieno-[2,3-d]pyrimidin-4-one

20.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[3-(4-(3-trifluoromethylphenyl)piperazin-1-yl)propyl]thieno-[2,3-d]pyrimidin-4-one×2HCl , m.p. 122-125° C.

21.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-naphth-1-ylpiperidin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one

22.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-methoxynaphth-1-yl)-3,4-dehydropiperidin-1-yl)ethyl]-thieno[2,3-d]pyrimidin-4-one

23.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-naphth-1-yl-1,4-hexahydro-1,4-diazepin-1-yl)ethyl]-thieno[2,3-d]pyrimidin-4-one,m.p. 225-230° C. (hydrochloride)

24.3,4-Dihydro-5-methyl-6-carbamoyl-3-[2-(4-(1-naphthyl)-piperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one

25.3,4-Dihydro-5-methyl-6-carbamoyl-3-[2-(4-pyrimidin-2-yl-piperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one

26.3,4-Dihydro-5-methyl-6-diethylcarbamoyl-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one

27.3,4-Dihydro-5-methyl-6-diethylcarbamoyl-3-[2-(4-(1-naphthyl)-piperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one

28.3,4-Dihydro-5-methyl-6-diethylcarbamoyl-3-[2-(4-pyrimidin-2-ylpiperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one

29.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-quinazolin-4-ylpiperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one,m.p. 295 - 300° C. (hydrochloride)

30.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2,4-dimethoxyphenyl)piperazin-1-yl)ethyl]thieno-[2,3-d]pyrimidin-4-one,m.p. 170-171° C.

31.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2,5-dimethylphenyl)piperazin-1-yl)ethyl]thieno-[2,3-d]pyrimidin-4-one,m.p. 90-91° C.

32.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-naphth-1-yl-3,4-dehydropiperidin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one,MS: m⁺=509.1

These compounds are suitable for treating central nervous system-relatedemotional disturbances such as seasonal affective disturbances anddysthymia. These disturbances also include anxiety states such asgeneralized anxiety, panic attacks, sociophobia, obsessional neurosesand post-traumatic stress symptoms, disturbances of the memory,including dementia, amnesias and age-related loss of memory, and alsopsychogenic eating disturbances such as anorexia nervosa and bulimianervosa.

DE 19724979.5 describes 3-substituted3,4,5,6,7,8-hexahydropyrido[3′,4′:4,5]thieno[2,3-d]pyrimidinederivatties of the formula I

where

R¹ is hydrogen, a C₁-C₄-alkyl group, an acetyl group, a phenylalkylC₁-C₄ radical, with the aromatic moiety optionally being substituted byhalogen or C₁-C₄-alkyl, trifluoromethyl, hydroxyl, C₁-C₄-alkoxy, amino,cyano or nitro groups, or a phenylalkanone radical, with it beingpossible for the phenyl group to be substituted by halogen,

R² is a phenyl, pyridyl, pyrimidinyl or pyrazinyl group which isoptionally monosubstituted or disubstituted by halogen atoms,C₁-C₄-alkyl or trifluoromethyl, trifluoromethoxy, hydroxyl,C₁-C₄-alkoxy, amino, monomethylamino, dimethylamino, cyano or nitrogroups and which can be optionally fused to a benzene nucleus which canbe optionally monosubstituted or disubstituted by halogen atoms orC₁-C₄-alkyl, hydroxyl, trifluoromethyl, C₁-C₄-alkoxy, amino, cyano ornitro groups and can optionally contain 1 nitrogen atom, or to a 5- or6-membered ring which can contain 1-2 oxygen atoms,

A is NH or oxygen,

Y is CH₂, CH₂—CH₂, CH₂—CH₂—CH₂ or CH₂—CH,

Z is nitrogen, carbon or CH, with it also being possible for the bondbetween Y and Z to be a double bond,

and n is the number 2, 3 or 4.

These compounds of the formula I can be prepared by reacting a compoundof the formula II

where R¹ has the abovementioned meanings, R³ is a cyano group or aC₁₋₃-alkyl-carboxylic ester group, and R⁴ is C₁₋₃-alkyl, with a primaryamine of the formula III

where R² has the abovementioned meanings, and, where appropriate,converting the resulting compound into the acid addition salt of aphysiologically tolerated acid.

The reaction expediently takes place in an inert organic solvent, inparticular a lower alcohol, e.g. methanol or ethanol, or a cyclic,saturated ether, in particular tetrahydrofuran or dioxane.

As a rule, the reaction takes place at from 20 to 110° C., in particularfrom 60 to 90° C., and has generally finished within from 1 to 10 hours.

Or, a compound of the formula II

where R¹ has the abovementioned meanings, R³ is a cyano group or aC₁₋₃-alkyl-carboxylic ester group, and R⁴ is C₁₋₃-alkyl, is reacted witha primary aminoalcqhol of the formula IV

in an inert solvent, preferably alcohols such as ethanol, at from 60° to120° C., in order to give the cyclization product V (X=OH)

which is subsequently converted into the corresponding halogenderivative V (X=Cl, Br) using a halogenating agent, such as thionylchloride or hydrobromic acid, in an organic solvent such as ahalogenohydrocarbon or without any solvent, at from room temperature to100° C. Finally, the halogen derivative of the formula V (X=Cl, Br) isreacted with an amine of the formula VI

where Y, Z and R² have the abovementioned meanings, to give the novelend product of the formula I. This reaction proceeds most efficiently inan inert organic solvent, preferably toluene or xylene, in the presenceof a base, such as potassium carbonate or potassium hydroxide, at from60° C. to 150° C.

The novel compounds of the formula I can either be purified byrecrystallization from the customary organic solvents, preferably from alower alcohol, such as ethanol, or by means of column chromatography.

The free 3-substituted pyrido[3′,4′:4,5]thieno[2,3-d]-pyrimidinederivatives of the formula I can be converted, in the customary manner,into the acid addition salts of a solution using the stoichiometricquantity of the corresponding acid. Examples of pharmaceuticallytolerated acids are hydrochloric acid, phosphoric acid, sulfuric acid,methanesulfonic acid, amidosulfuric acid, maleic acid, fumaric acid,oxalic acid, tartaric acid and citric acid.

The following Examples serve to clarify the invention:

A Preparation of the starting materials

a)2-Amino-3-carboethoxy-5-ethyl-4,5,6,7-tetrahydrothieno-[3,2-c]pyridine

62.9 ml (588 mmol) of ethyl cyanoacetate and 18.8 g (588 mmol) ofpowdered sulfur were added to 96.1 g (588 mmol) of 1-ethyl-3-piperidonex HCl in 350 ml of ethanol, and 150 ml (1080 mmol) of triethylamine werethen added under a nitrogen atmosphere and while stirring thoroughly.After 0.5 h, the mixture was heated to reflux for 6 h and then left tostir at room temperature overnight. The reaction mixture was poured onto3 l of ice water and the resulting mixture was adjusted to pH=9 andextracted twice with methylene chloride. After the organic phase hadbeen dried and evaporated, the crude product was purified by columnchromatography (silica gel, eluent methylene chloride/methanol 93/7).29.2 g (20%) of product were isolated as slightly oily solids.

b)2-Ethoxymethyleneamino-3-carboethoxy-5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

0.5 ml of acetic anhydride was added to 3.8 g (14.9 mmol) of2-amino-3-carboethoxy-5-ethyl-4,5,6,7-tetrahydrothieno-[3,2-c]pyridinein 40 ml of triethyl orthoformate, and the mixture was boiled undernitrogen and at reflux for 1 h. After the mixture had been decanted offfrom the insoluble black coating on the flask walls, it was thenevaporated right down at 80° C. on a rotary evaporator. 3.5 g (94%) ofcrude product were isolated as a dark oil which is sufficiently pure forfurther reaction.

The 5-acetyl derivatives were prepared from 1-acetyl-3-piperidone inanalogy with a) and b) (P. Krogsgaard-Larsen, H. Hjeds: Acta Chem. ScandB 30, 884 (1976)).

c)3-(2-Hydroxyethyl)-6-ethyl-3,4,5,6,7,8-hexahydropyrido-[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one

5.0 ml (81 mmol) of ethanolamine were added to 17.0 g (55 mmol) of2-ethoxymethyleneamino-3-carboethoxy-5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridinein 130 ml of ethanol, and the mixture was boiled at reflux for 2 h. Themixture was then evaporated down to a volume of approx. 50 ml and thiswas thoroughly stirred in an ice bath. The fine solids whichprecipitated out were filtered off with suction and then washed withcold ethyl acetate. 10.5 g (63%) of a pale brown product were isolated.

d)3-(2-Chloroethyl)-6-ethyl-3,4,5,6,7,8-hexahydropyrido-[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one

10.5 g (37.6 mmol) of3-(2-hydroxyethyl)-6-ethyl-3,4,5,6,7,8-hexahydropyrido[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-onein 100 ml of 1,2-dichloroethane were heated to reflux (slowdissolution), after which 3.5 ml (48 mmol) of thionyl chloride in 20 mlof 1,2-dichloroethane were added dropwise. After 1 h of reflux boiling,the reaction mixture was allowed to cool down and the solid was filteredoff with suction; it was then rewashed with 1,2-dichloroethane. Thecrude product was partitioned between methylene chloride and water atpH=9. After the organic phase had been dried and concentrated, 9.3 g(83%) of product were isolated as a dark oil, which slowly crystallizesthroughout and which is sufficiently pure for the subsequent reactions,m.p. 94-96° C.

e) N-(1-Naphthyl)piperazine

83.2 g (966 mmol) of piperazine, 38.0 g (339 mmol) of potassiumtert-butoxide and 50.0 g (241 mmol) of 1-bromonaphthalene were added toa mixture of 5.4 g (24.2 mmol) of palladium acetate and 14.7 g (48.3mmol) of tri-o-tolylphosphine in 500 ml of xylene, and the reactionmixture was heated at reflux for 10 h under a nitrogen atmosphere andwhile stirring thoroughly. After that, the mixture was diluted withmethylene chloride, the insoluble residues were filtered off and thefiltrate was evaporated. The crude product was purified by columnchromatography (silica gel, eluent THF/methanol/ammonia 85/13/2). 21.5 g(42%) of product having a m.p. of 84-86° C. were isolated.

f) N-(2-Methyl-1-naphthyl)piperazine

14.7 g (82.7 mmol) of bis(2-chloroethyl)amine×HCl were added to 13.0 g(82.7 mmol) of 1-amino-2-methylnaphthalene in 100 ml of chlorobenzene,and the mixture was boiled under nitrogen and at reflux for 90 h. Themixture was subsequently evaporated and the residue was partitionedbetween methylene chloride and water at pH=9; the organic phase was thenevaporated after having been dried. The crude product was purified bycolumn chromatography (silica gel, eluent THF/methanol/ammonia 85/13/2.11.6 g (62%) of product were isolated.

g) 4-Piperazin-1-ylisoquinoline

4.51 g (21.7 mmol) of 4-bromoisoquinoline, 4.65 g (25.0 mmol) of t-butylpiperazine-N-carboxylate, 0.1 g (0.11 mmol) oftris(dibenzylideneacetone)dipalladium, 0.11 g (0.18 mmol) of2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 2.92 g (30.4 mmol) ofsodium tert-butoxide were together added to 50 ml of toluene and themixture was stirred at 75° C. for 2 h. The reaction mixture was added toice/sodium chloride and the resulting mixture was extracted with ethylacetate; the organic phase was then dried over sodium sulfate and thesolvent was removed on a rotary evaporator. The product crystallized outand was filtered off with suction and washed with pentane. 5.5 g (81%)of the Boc-protected piperazine were obtained (m.p.: 111° C.). 5.2 g(16.6 mmol) of this substance were taken up in 17 ml of dichloromethane,after which 17 ml (0.22 mmol) of trifluoroacetic acid were added slowlyat 0° C. The mixture was left to stir at 0° C. for 4 h, after which itwas poured onto ice water and the resulting mixture was extracted withdichloromethane. The aqueous phase was filtered, rendered alkaline andthen extracted with dichloromethane. After having dried over sodiumsulfate and to a large extent having removed the solvent, dilution waseffected with diethyl ether and the hydrochloride was precipitated withethereal hydrochloric acid. 3.2 g (67%) of the product, having a m.p. of293-294° C., were obtained.

Insofar as they were not known from the literature, additionalpiperazine derivatives (see Examples) were prepared in analogy with e),f) and g) (cf. Patent Application DE 19636769.7 as well).

B Preparation of the end products

EXAMPLE 13,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one×3HCl×2H₂O

2.3 g (10.0 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)-piperazinewere added to 3.1 g (10.0 mmol) of2-ethoxymethyleneamino-3-carboethoxy-5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridinein 50 ml of ethanol, and the mixture was boiled at reflux for 1 h. Afterthat, the mixture was evaporated on a rotary evaporator and the crudeproduct was purified by column chromatography (silica gel, eluentmethylene chloride/methanol 93/7). 2.9 g (48%) of product, having a m.p.of 172-174° C., were isolated following conversion into thehydrochloride in ethyl acetate.

EXAMPLE 23,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-(2-methoxy-1-naphthyl)-piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one×2HCl×2 H₂O

1.3 g (4.5 mmol) of N-(2-methoxy-1-naphthyl)piperazine and 0.65 g (4.5mmol) of finely powdered potassium carbonate were added to 1.1 g (4.5mmol) of3-(2-chloroethyl)-6-ethyl-3,4,5,6,7,8-hexahydropyrido[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-onein 40 ml of xylene, and the mixture was boiled under a nitrogenatmosphere and at reflux for a total of 70 h. The mixture was thenevaporated under reduced pressure and the residue was partitioned atpH=10 between methylene chloride and water. After the organic phases hadbeen dried and evaporated, the crude product was purified by columnchromatography (silica gel, eluent acetone). 1.1 g (50%) of producthaving a m.p. of 232-234° C. (decomp.), were isolated.

The following were prepared in analogy with Examples 1 and 2:

1.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-(2-methyl-1-naphthyl)-piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one×2HCl×3 H₂O, m.p. 238-240° C. (decomp.)

2.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-(1-naphthyl)piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one×2HCl×3H₂O, m.p. 298-300° C. (decomp.)

3.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-(2-methylphenyl)-piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

4.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-(2,3-dimethylphenyl)-piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

5.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-(2-chlorophenyl)-piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 148-150° C.

6.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-pyrimidin-2-yl-piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

7.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-pyridin-2-ylpiperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one

8.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-quinolin-2-ylpiperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one

9.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-(2-methoxyphenyl)-piperidin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

10.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-(2-methoxyphenyl)-3,4-dehydropiperidin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

11.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[3-(4-pyrimidin-2-yl-piperazin-1-yl)propyl]pyrido[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one×3HCl×4 H₂O, m.p. 211-213° C. (decomp.)

12.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-tetralin-5-yl-piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one,m.p. 287° C. (hydrochloride)

13.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-indan-1-ylpiperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one

14.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one×2HCl×H₂O, m.p. 138-140° C.

15.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-(2-cyanophenyl)-piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one

16.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-isoquinolin-4-yl-piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

17.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-naphth-1-ylhexahydro-1,4-diazepin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one,m.p. 276-280° C. (hydrochloride)

18.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-naphth-1-yl-3,4-dehydropiperidin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one,MS: m⁺=507.1

19.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-naphth-1-ylpiperidin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one

20.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[2-(4-(2-methoxynaphth-1-yl-3,4-dehydropiperidin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one

21.3,4,5,6,7,8-Hexahydro-6-ethyl-3-[3-(4-phenylpiperidin-1-yl)-propylpyrido[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one,m.p. 241° C. (hydrochloride)

22.3,4,5,6,7,8-Hexahydro-6-acetyl-3-[2-(4-(2-methoxyphenyl)-piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

23.3,4,5,6,7,8-Hexahydro-6-acetyl-3-[2-(4-(2-methyl-1-naphthyl)-piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

24.3,4,5,6,7,8-Hexahydro-6-acetyl-3-[2-(4-(2-methoxy-1-naphthyl)piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one

The acetyl group in the 6 position can, in analogy with DE 19 636 769.7,be eliminated with 10 percent hydrochloric acid, while boiling underreflux, to give the corresponding secondary amines. The alkylations atN-6 to give the 6-alkyl derivatives can likewise be performed asdescribed in DE 19 636 769.7.

25.3,4,5,6,7,8-Hexahydro-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one

26.3,4,5,6,7,8-Hexahydro-6-benzyl-3-[2-(4-(2-methylphenyl)-piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]-pyrimidin-4-one

27.3,4,5,6,7,8-Hexahydro-6-(4-chlorophenyl-2-ethyl)-3-[2-(4-(1-naphthyl)piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]-thieno[2,3-d]pyrimidin-4-one

28.3,4,5,6,7,8-Hexahydro-6-(4-methoxybenzyl)-3-[2-(4-(2-methyl-1-naphthyl)piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno-[2,3-d]pyrimidin-4-one

29.3,4,5,6,7,8-Hexahydro-6-benzyl-3-[2-(4-(1-naphthyl)piperazin-1-yl)ethyl]pyrido[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one×2HCl×H₂O, m.p. 268-270° C.

These compounds are suitable for treating central nervous system-relatedemotional disturbances such as seasonal affective disturbances anddysthymia. These disturbances also include anxiety states such asgeneralized anxiety, panic attacks, sociophobia, obsessional neurosesand post-traumatic stress symptoms, disturbances of the memory,including dementia, amnesias and age-related loss of memory, and alsopsychogenic eating disturbances such as anorexia nervosa and bulimianervosa.

It has now been found that pyrimidine derivatives of the formula I

where

A is NH or oxygen,

B is hydrogen or methyl,

C is hydrogen, methyl or hydroxyl,

D is methyl,

 D and E are together —CH₂—CH₂—NR¹—CH₂—, —CH₂—NR¹—CH₂— or—CH₂—NR¹—CH₂—CH₂—,

X is nitrogen,

Y is CH₂, CH₂—CH₂, CH₂—CH₂—CH₂ or CH₂—CH,

Z is nitrogen, carbon or CH, with it also being possible for the bondbetween Y and Z to be a double bond,

n is the number 2, 3 or 4,

R¹ is hydrogen, a C₁-C₄-alkyl group, an acetyl or benzoyl group, aphenylalkyl C₁-C₄ radical or phenylalkoxy C₂-C₅ radical, with thearomatic moiety optionally being substituted by halogen, or C₁-C₄-alkyl,trifluoromethyl, hydroxyl, C₁-C₄-alkoxy, amino, cyano or nitro groups, anaphthylalkyl C₁-C₃ radical, a phenylalkanone C₂-C₄ radical or a phenyl-or pyridylcarbamoylalkyl C₂ radical, with it being possible for thephenyl or pyridyl group to be substituted by halogen, a C₁-C₃-alkylgroup, a methoxy group and by a nitro or amino group,

R² is a phenyl, pyridyl, pyrimidinyl or pyrazinyl group which isoptionally monosubstituted, disubstituted or trisubstituted by halogenatoms, C₁-C₄-alkyl or trifluoromethyl, trifluoromethoxy, hydroxyl,C₁-C₄-alkoxy, amino, monomethylamino, dimethylamino, cyano or nitrogroups and which can optionally be fused to a benzene nucleus which canoptionally be monosubstituted or disubstituted by halogen atoms,C₁-C₄-alkyl or hydroxyl, trifluoromethyl, C₁-C₄-alkoxy, amino, cyano ornitro groups and which can optionally contain 1 nitrogen atom, or to a5- or 6-membered ring which can contain 1-2 oxygen atoms, or can besubstituted by a phenyl-C₁-C₂-alkyl- or -alkoxy group, with it beingpossible for the phenyl radical to be substituted by halogen, or amethyl, trifluoromethyl or methoxy group,

R³ and R⁴ are, independently of each other, hydrogen or a C₁-C₄-alkylgroup,

and their physiologically tolerated salts,

are suitable for producing medicaments for the prophylaxis and therapyof neurodegeneration, brain trauma and cerebral ischemia, in particularstrokes, or for the prophylaxis and therapy of the sequelae which arecaused by these diseases.

A use according to the invention also concerns neuroprotection.

The preparation of these pyrimidine derivatives is described in thepatent specifications which were mentioned at the outset.

A medicament is produced using a compound of the formula I, or itspharmacologically tolerated acid addition salt, as the active compound,together with customary excipients and diluents.

The use according to the invention can be effected, in the customarymanner, orally or parenterally, intravenously or intramuscularly.

The dose depends on the age, condition and weight of the patient and onthe type of administration. As a rule, the daily dose of active compoundis from about 1 to 100 mg/kg of body weight in the case of oraladministration and from 0.1 to 10 mg/kg of body weight in the case ofparenteral administration.

The medicaments can be used in the usual pharmaceutical administrationforms in the solid or liquid state, e.g. as tablets, film tablets,capsules, powders, granules, coated tablets, suppositories, solutions,ointments, creams or sprays. These forms are produced in the customarymanner. In this context, the active compounds can be worked up with thecustomary pharmaceutical auxiliary substances such as tablet binders,fillers, preservatives, tablet disintegrants, flow regulators,plasticizers, crosslinking agents, dispersants, emulsifiers, solvents,delayed release agents, antioxidants and/or propellant gases (cf. H.Sucker et. al: Pharmazeutische Technologie (Pharmaceutical Technology),Thieme-Verlag, Stuttgart, 1978). The resulting administration formsnormally comprise the active compound in a quantity of from 1 to 99% byweight.

What is claimed is:
 1. A method of preventing or treating cerebralischemia or strokes in a mammal in need of such treatment comprisingadministering to said mammal an effective amount of pyrimidinederivatives of the formula I

where A is NH or oxygen, B is hydrogen or methyl, C is hydrogen, methylor hydroxyl, D is methyl, E is

 D and E are together —CH₂—CH₂—NR¹—CH₂—, —CH₂—NR¹—CH₂— or—CH₂—NR¹—CH₂—CH²—, X is nitrogen, Y is CH₂, CH₂—CH₂, CH₂—CH₂CH₂ orCH₂—CH, Z is nitrogen, carbon or CH, with it also being possible for thebond between Y and Z to be a double bond, n is the number 2, 3, or 4, R¹is hydrogen, a C₁-C₄-alkyl group, an acetyl or benzoyl group, aphenylalkyl C₁-C₄ radical or phenylalkoxy C₂-C₅ radical, with thearomatic moiety optionally being substituted by halogen, or C₁-C₄-alkyl,trifluoromethyl, hydroxyl, C₁-C₄-alkoxy, amino, cyano or nitro groups, anaphthylalkyl C₁-C₃ radical, a phenylalkanone C₂-C₄ radical or a phenyl-or pyridylcarbamoylalkyl C₂ radical, with it being possible for thephenyl or pyridyl group to be substituted by halogen, a C₁-C₃-alkylgroup, a methoxy group and by a nitro or amino group, R² is a phenyl,pyridyl, pyrimidinyl or pyrazinyl group which is optionallymonosubstituted, disubstituted or trisubstituted by halogen atoms,C₁-C₄-alkyl or trifluoromethyl, trifluoromethoxy, hydroxyl,C₁-C₄-alkoxy, amino, monomethylamino, dimethylamino, cyano, thiomethylor nitro groups and which can optionally be fused to a benzene nucleuswhich can optionally be monosubstituted or disubstituted by halogenatoms, C₁-C₄-alkyl or hydroxyl, trifluoromethyl, C₁-C₄-alkoxy, amino,cyano or nitro groups and which can optionally contain 1 nitrogen atom,or to a 5- or 6-membered ring which can contain 1-2 oxygen atoms, or canbe substituted by a phenyl-C₁-C₂-alkyl- or -alkoxy group, with it beingpossible for the phenyl radical to be substituted by halogen, or amethyl, trifluoromethyl or methoxy group, R³ and R⁴ are, independentlyof each other, hydrogen or a C₁-C₄-alkyl group, or their physiologicallytolerated salts.